Substituted phenoxybenzamides

ABSTRACT

The present invention relates to substituted phenoxybenzamide compounds of general formula (I): in which R 1 , R 2 , R 3 , R 4 , R 5 , X, R 6  and q are as defined in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.

FIELD OF THE INVENTION

The present invention relates to substituted phenoxybenzamide compoundsof general formula (I) as described and defined herein, to methods ofpreparing said compounds, to pharmaceutical compositions andcombinations comprising said compounds and to the use of said compoundsfor manufacturing a pharmaceutical composition for the treatment orprophylaxis of a disease, in particular of a hyper-proliferative and/orangiogenesis disorder, as a sole agent or in combination with otheractive ingredients.

BACKGROUND OF THE INVENTION

Cancer is a disease resulting from an abnormal growth of tissue. Certaincancers have the potential to invade into local tissues and alsometastasize to distant organs. This disease can develop in a widevariety of different organs, tissues, and cell types. Therefore, theterm “cancer” refers to a collection of over a thousand differentdiseases.

Over 4.4 million people worldwide were diagnosed with breast, colon,ovarian, lung, or prostate cancer in 2002 and over 2.5 million peopledied of these devastating diseases (Globocan 2002 Report). In the UnitedStates alone, over 1.25 million new cases and over 500,000 deaths fromcancer were predicted in 2005. The majority of these new cases wereexpected to be cancers of the colon (˜100,000), lung (˜170,000), breast(˜210,000) and prostate (˜230,000). Both the incidence and prevalence ofcancer is predicted to increase by approximately 15% over the next tenyears, reflecting an average growth rate of 1.4% [1].

Accumulating evidence suggests that cancer can be envisioned as a“signaling disease”, in which alterations in the cellular genomeaffecting the expression and/or function of oncogenes and tumorsuppressor genes would ultimately affect the transmission of signalsthat normally regulate cell growth, differentiation, and programmed celldeath (apoptosis). Unraveling the signaling pathways that aredysregulated in human cancers has resulted in the design of anincreasing number of mechanism-based therapeutic agents [2]. Signaltransduction inhibition as a therapeutic strategy for human malignancieshas recently met with remarkable success, as exemplified by thedevelopment of Gleevec for the treatment of chronic myelogenous leukemia(CML) and gastrointestinal stromal tumors (GIST), heralding a new era of“molecularly-targeted” therapies [3-5].

The mitogen-activated protein kinase (MAPK) module is a key integrationpoint along the signal transduction cascade that links diverseextracellular stimuli to proliferation, differentiation and survival.Scientific studies over the last twenty years have led to a quitedetailed molecular dissection of this pathway, which has now grown toinclude five different MAPK subfamilies [extracellular signal-regulatedkinases ERK-1/2, c-Jun-N-terminal kinases (JNKs), p38 kinases, ERK-3/4,and ERK-5], with distinct molecular and functional features [6-8]. Whilecertain subfamilies, such as the p38 family, are becoming therapeutictargets in inflammatory and degenerative diseases, the MAPK cascade thatproceeds from Ras to ERK-1/2 (the main mitogenic pathway initiated bypeptide growth factors) is starting to emerge as a prime target for themolecular therapy of different types of human cancers [9-11], The MAPKpathway is aberrantly activated in many human tumors as a result ofgenetic and epigenetic changes, resulting in increased proliferation andresistance to apoptotic stimuli. In particular, mutated oncogenic formsof Ras are found in 50% of colon and >90% of pancreatic cancers [12].Recently, BRAF mutations have been found in >60% of malignant melanoma[13]. These mutations result in a constitutively activated MAPK pathway.In addition, overexpression of or mutational activation of certainreceptor tyrosine kinases can also lead to increased activation of theRaf-MEK-ERK pathway.

The modular nature of the Raf/MEK/ERK cascade becomes less pleiotropicat the crossover point that is regulated by MEK [14]. No substrates forMEK have been identified other than ERK-1/2. Phosphorylated ERK is theproduct of MEK activity and thus its detection in cancer cells and intumor tissues provides a direct measure of MEK inhibition. Theselectivity of MEK for ERK1/2 coupled with the availability ofantibodies specific for the dually phosphorylated and activated form ofERK, makes MEK an attractive target for anticancer drug development. Inaddition, it was recently shown that MEK activation regulates matrixmineralization (Blood 2007, 40, 68), thereby modulation of MEK activitymay also be applicable for the treatment of diseases caused by oraccompanied with dysregulation of tissue mineralization, morespecifically for the treatment of diseases caused by or accompanied withdysregulation of bone mineralization.

First-generation MEK inhibitors, PD98059 [15] and U0126 [16], do notappear to compete with ATP and thus are likely to have distinct bindingsites on MEK; these compounds have been extensively used in modelsystems in vitro and in vivo to attribute biological activities toERK1/2. A second-generation MEK1/2 inhibitor, PD184352 (now calledCI-1040), has an IC₅₀ in the low nanomolar range, enhancedbioavailability, and also appears to work via an allosteric, nonATP-competitive mechanism [17]. Oral treatment with CI-1040 has beenshown to inhibit colon cancer growth in vivo in mouse models [18] andthis compound was evaluated in phase I/II clinical trials in humanswhere it eventually failed because of insufficient efficacy [19].Further allosteric MEK inhibitors have recently entered the clinic butwere found to have limitations such as poor exposure profiles, limitedefficacy and/or toxicity issues. Small molecules MEK inhibitors havebeen disclosed, including in US Patent Publications Nos. 2003/0232869,2004/0116710, 2003/0216420 and in U.S. patent applications Ser. Nos.10/654,580 and 10/929, 295 each of which is hereby incorporated byreference. A number of additional patent applications have appeared inthe last few years including U.S. Pat. No. 5,525,6625; WO 98/43960; WO99/01421; WO 99/01426; WO 00/41505; WO 00/41994; WO 00/42002; WO00/42003; WO 00/42022; WO 00/42029; WO 00/68201; WO 01/68619; WO02/06213; WO 03/077914; WO 03/077855; WO 04/083167; WO 05/0281126; WO05/051301; WO 05/121142; WO 06/114466; WO 98/37881; WO 00/35435; WO00/35436; WO 00/40235; WO 00/40237; WO 01/05390; WO 01/05391; WO01/05392; WO 01/05393; WO 03/062189; WO 03/062191; WO 04/056789; WO05/000818; WO 05/007616; WO 05/009975; WO 05/051300; WO05/051302; WO05/028426; WO 06/056427; WO 03/035626; and WO 06/029862.

Despite advancements in the art, there remains a need for cancertreatments and anti-cancer compounds. More specifically, there remains aneed for structurally novel MEK inhibitors with a balancedpotency-properties profile. It would be especially desirable to identifynovel MEK inhibitors which incorporate structural motifs which have notbeen previously exemplified as being compatible with potent MEKinhibition. It would be especially favorable if these structural motifswould further allow for improvement of MEK potency and/or modulation ofcompound properties (including physico-chemical, pharmacodynamical andpharmacokinetical properties).

It is now found that compounds of the present invention are potent andselective MEK inhibitors. The compounds of the present invention arederived from a 1-substituted-2-phenylamino-phenyl scaffold with afurther specifically substituted side chain in the 6-position of thephenyl scaffold. This finding is surprising as inspection of publishedphenyl-scaffold-derived MEK inhibitors and previous structure-activityrelationship analysis (see for example Haile Tecle/Pfizer GlobalResearch: “MEK inhibitors”, presented at Drew University, 15^(th) Jun.2006) suggested that in phenyl-scaffold-based MEK inhibitors larger6-substituents are detrimental for achieving high MEK inhibitorypotency. Compounds of the present invention are potent MEK inhibitorsand inhibit activation of the MEK-ERK pathway. Compounds andcompositions described herein, including salts, metabolites, solvates,solvates of salts, hydrates, prodrugs such as esters, polymorphs, andstereoisomeric forms thereof, exhibit anti-proliferative activity andare thus useful to prevent or treat the disorders associated withhyper-proliferation.

DESCRIPTION OF THE INVENTION

The present invention thus relates to compounds of general formula (I):

in which:

-   R¹ and R² are the same or different and are independently a hydrogen    atom, a halogen atom, a C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,    or —CN group, in which at least one of R¹ and R² is a halogen atom;-   R³ is, in each occurrence, independently, a halogen atom, a    C₁-C₄-alkyl or —CN group;-   q is an integer of 0, 1, 2, or 3;-   R⁴ is a hydrogen atom or a C₁-C₆-alkyl group;-   R⁵ is a —C(═O)R⁷, —C(═O)OR⁷, —C(═O)N(R⁷)(R⁸), —NHC(═O)R⁷, —S(═O)₂R⁷,    —NHS(═O)₂R⁷, —S(═O)₂NR⁷R⁸, —NO₂, —CN, or a

-   -   in which:    -   each of Z¹, Z², Z³ and Z⁴ is independently —CH—,        —C(C₁-C₆-alkyl)-, —C(═O)—, —S—, —O—, —N— or —NH, such that at        least one of Z¹, Z², Z³ and Z⁴ is —N— or —NH—;

-   X is —O—, —NH—, —N(C₁-C₆-alkyl)-, —S—, —S(═O)₂—, —C(═O)—, —C(═O)O—,    or —C(═O)NH—;

-   R⁶ is —(CR¹⁵ ₂)_(n)—(CR¹⁵(OR¹¹))—(CR¹⁵ ₂)_(m)—R⁹, or —(CH₂)_(n)—Y

-   Y is:    -   a) an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group,        said aryl, heteroaryl, cycloalkyl or heterocycloalkyl group        being substituted with one or more —(CH₂)_(o)Y′ groups, in each        occurrence of said —(CH₂)_(o)Y′ group:        -   o is an integer of 0; and        -   Y′ is, independently:            -   a C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxyalkyl,                cycloalkyl, or heterocycloalkyl group,        -   or            -   an —OR^(c′) group, in each occurrence of which, R^(c′)                is, independently:                -   a —C(═O)R^(e) group, in which R^(e) is defined                    infra, or                -   an —S(═O)₂R^(e) group, in which R^(e) is defined                    infra, or                -   a C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl,                    aryl, or heteroaryl group, in which C₁-C₆-haloalkyl,                    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl                    group, are, independently of each other, optionally                    substituted one or more times with:                -    a halogen atom, or                -    an —OH, or                -    an aryl group, or                -    an —OR^(f) group, in which R^(f) is as defined                    infra, or                -    an —NR^(d1)R^(d2) group, in which R^(d1) and R^(d2)                    are as defined infra, or                -    a —OP(═O)(OR^(f))₂ group, in which R^(f) is as                    defined infra;        -   or            -   an —NR^(d1)R^(d2) group, as defined infra, with the                provisos that:                -   when one of R^(d1) and R^(d2) is H, then the other                    of R^(d1) and R^(d2) is neither H nor C₁-C₆-alkyl,                    and                -   R^(d1) and R^(d2) cannot simultaneously be                    C₁-C₆-alkyl;        -   or            -   an —NR^(a)S(═O)₂R^(b) group, as defined infra, with the                proviso that:                -   when R_(a) is H, then R_(b) is not C₁-C₆-alkyl;        -   Or            -   an —S(═O)₂R^(b) group, in which R^(b) is as defined                infra, with the provisos that when R^(b) is                —NR^(d1)R^(d2):                -   R^(d1) and R^(d2) are not both H,                -   when R^(d1) is H, then R^(d2) is not C₁-C₆-alkyl,                -   R^(d1) and R^(d2) are not both C₁-C₆-alkyl,        -   or            -   a —C(═O)R^(b) group, in which R^(b) is as defined infra;    -   or    -   b) an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group,        said aryl, heteroaryl, cycloalkyl or heterocycloalkyl group        being substituted with one or more —(CH₂)_(o)R¹⁴ groups, in each        occurrence of said —(CH₂)_(o)R¹⁴ group:        -   o is an integer of 1 or 2; and        -   R¹⁴ is as defined infra;    -   or    -   c) a C₂-C₁₀-alkenyl or C₅-C₁₀-cycloalkenyl group, said        C₂-C₁₀-alkenyl or C₅-C₁₀-cycloalkenyl group being optionally        substituted with one or more —(CH₂)_(o)R¹⁴ groups, in which o        and R¹⁴ are as defined infra

-   R⁷ and R⁸ are independently a hydrogen atom, a —N(R¹²)(R¹³), —OH,    —C₁-C₆-alkoxy, C₁-C₆-alkyl, —CF₃,    —O—(CH₂)_(n)—(CH(OR¹¹))—(CH₂)_(m)—R⁹, —O—(CH₂)_(n)-cycloalkyl, aryl,    heteroaryl, cycloalkyl or heterocycloalkyl group, in which aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of    each other, optionally substituted with one or more halogen atoms,    C₁-C₆-alkyl or C₁-C₆-alkoxy groups;

-   R⁹ and R¹⁰ are independently —OH, —C₁-C₆-alkoxy, halogen,    heteroaryl, —NR^(d1)R^(d2) or —N(R¹²)(R¹³);

-   R¹¹, R¹² and R¹³:    -   are independently a hydrogen atom, a C₁-C₆-alkyl, aryl,        heteroaryl, cycloalkyl or heterocycloalkyl group, in which        C₁-C₆-alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl        are, independently of each other, optionally substituted with        one or more —(CH₂)_(o)R¹⁴ groups,

-   or

-   R¹² and R¹³, together with the N atom to which they are bound, form    a 5-, 6-, or 7-membered heterocyclic ring which optionally comprises    one or more additional heteroatoms, which optionally comprises one    or more —C(═O)— or —S(═O)₂ groups, and which is optionally    substituted with one or more —(CH₂)_(o)R¹⁴ groups;

-   R¹⁴ is, in each occurrence, independently, a halogen atom, a    C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxyalkyl, cycloalkyl,    heterocycloalkyl, —OR^(c), —NR^(d1)R^(d2), —CN, —NHS(═O)₂H,    —NR^(a)S(═O)₂R^(b), —S(═O)₂R^(b) or —C(═O)R^(b) group;

-   R¹⁵ is, in each occurrence, independently, a hydrogen atom or a    C₁-C₆-alkyl group, in which at least one R¹⁵ groups is C₁-C₆-alkyl;

-   n is, in each occurrence, independently, an integer of 0, 1, 2, 3,    or 4;

-   m is, in each occurrence, independently, an integer of 0, 1, or 2;    and

-   o is, in each occurrence, independently, an integer of 0, 1, or 2;

-   R^(a) is, in each occurrence, independently, a hydrogen atom or a    C₁-C₆-alkyl group;

-   R^(b) is, in each occurrence, independently, an —OH, —OR^(c),    —SR^(c), —NR^(d1)R^(d2), a C₁-C₆-alkyl, aryl, heteroaryl, cycloalkyl    or heterocycloalkyl group, in which C₁-C₆-alkyl, heteroaryl,    cycloalkyl and heterocycloalkyl are, independently of each other,    optionally substituted one or more times with a halogen atom, an    —OH, C1-C6-alkyl or C₁-C₆-alkoxy group;

-   R^(c) is, in each occurrence, independently, a hydrogen atom, a    —C(═O)R^(e), —S(═O)₂R^(e), C₁-C₆-alkyl, C₁-C₆-haloalkyl cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl group, in which C₁-C₆-alkyl,    C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,    are, independently of each other, optionally substituted one or more    times with a halogen atom, an —OH, aryl, —OR^(f), —NR^(d1)R^(d2), or    —OP(═O)(OR^(f))₂ group;

-   R^(d1), R^(d2), R^(d1), R^(d2):    -   are, in each occurrence, independently of each other, a hydrogen        atom, a C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, —C(═O)R^(e), —S(═O)₂R^(e), or —C(═O)NR^(g1)R^(g2)        group, in which C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl are, independently of each other, optionally        substituted one or more times, the same way or differently, with        a halogen atom, a C₁-C₆-alkyl, an —OH or aryl, —NR^(g1)R^(g2),        —OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or —OP(═O)(OR^(f))₂ group;

-   Or

-   R^(d1) and R^(d2), together with the nitrogen atom to which they are    bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered    heterocycloalkyl ring, which is optionally substituted one or more    times, the same way or differently, with a halogen atom, a    C₁-C₆-alkyl, —NR^(g1)R^(g2), —OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or    —OP(═O)(OR^(f))₂ group; and the carbon backbone of which is    optionally interrupted one or more times, in the same way or    differently, with NH, NR^(d3), O, or S, and is optionally    interrupted one or more times, in the same way or differently, with    a —C(═O)—, —S(═O)—, and/or —S(═O)₂— group, and optionally contains    one or more double bonds;

-   R^(d3) is a hydrogen atom, a C₁-C₆-alkyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl group, in which C₁-C₆-alkyl or    cycloalkyl are, independently of each other, optionally substituted    one or more times with a halogen atom, an —OH, C₁-C₆-alkyl,    cycloalkyl, C₁-C₆-haloalkyl or C₁-C₆-alkoxy group;

-   R^(e) is an —NR^(g1)R^(g2), C₁-C₆-alkyl, cycloalkyl, C₁-C₆-alkoxy,    aryl or heteroaryl group;

-   R^(f) is a hydrogen atom, a —C(═O)R^(e), C₁-C₆-alkyl,    C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl    group, in which C₁-C₆-alkyl, C₁-C₆-haloalkyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl are, independently of each    other, optionally substituted one or more times with a halogen atom,    an —OH, C₁-C₆-alkoxy, aryl, or —NR^(g1)R^(g2) group;

-   R^(g1), R^(g2) are, independently of each other, a hydrogen atom, a    C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl    group; or

-   R^(g1) and R^(g2) together with the nitrogen atom to which they are    bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered    heterocycloalkyl ring, which is optionally substituted one or more    times, in the same way or differently, with a halogen atom, an —OH,    C₁-C₆-alkyl, C₁-C₆-alkoxy group; and the carbon backbone of which is    optionally interrupted one or more times, in the same way or    differently, with NH, NR^(a), O, S, and is optionally interrupted    one or more times, in the same way or differently, with a —C(═O)—,    —S(═O)—, and/or —S(═O)₂— group, and optionally contains one or more    double bonds;

-   with the proviso that:

-   X—R⁶ is not (O or NH)—(CH₂)_(r)—R^(r),    -   where R^(r) is NR^(s1)R^(s2) in which    -   r=1-4, and    -   R^(s1), R^(s2)=independently hydrogen, C₁-C₈ alkyl, or taken        together with the nitrogen to which they are attached, form a        3-10 member cyclic ring optionally containing one oxygen atom or        one sulfur atom or one NH or N—C₁-C₈ alkyl group;

-   or a tautomer, stereoisomer, physiologically acceptable salt,    hydrate, solvate, metabolite, or prodrug thereof.

In accordance with a particular embodiment, the present inventionrelates to compounds of general formula (I):

-   R¹ and R² are the same or different and are independently a halogen    atom, a methyl, or C₂-alkynyl group, in which at least one of R¹ and    R² is a halogen atom;-   R³ is, in each occurrence, a halogen atom;-   q is an integer of 1, 2, or 3;-   R⁴ is a hydrogen atom;    -   R⁵ is a —C(═O)R⁷ or —C(═O)N(R⁷)(R⁸) group;-   X is —O—;-   R⁶ is —(CR¹⁵ ₂)_(n)—(CR¹⁵(OR¹¹))—(CR¹⁵ ₂)_(m)—R⁹, or —(CH₂)_(n)—Y;-   Y is:    -   a) an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group,        said aryl, heteroaryl, cycloalkyl or heterocycloalkyl group        being substituted with one or more —(CH₂)_(o)Y′ groups, in each        occurrence of said —(CH₂)_(o)Y′ group:        -   o is an integer of 0; and        -   Y′ is, independently:            -   a C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxyalkyl,                cycloalkyl, or heterocycloalkyl group,        -   Or            -   an —OR^(c′) group, in each occurrence of which, R^(c′)                is, independently:                -   a —C(═O)R^(e) group, in which R^(e) is defined                    infra, or                -   an —S(═O)₂R^(e) group, in which R^(e) is defined                    infra, or                -   a C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl,                    aryl, or heteroaryl group, in which C₁-C₆-haloalkyl,                    cycloalkyl, heterocycloalkyl, aryl, or heteroaryl                    group, are, independently of each other, optionally                    substituted one or more times with:                -    a halogen atom, or                -    an —OH, or                -    an aryl group, or                -    an —OR^(f) group, in which R^(f) is as defined                    infra, or                -    an —NR^(d1)R^(d2) group, in which R^(d1) and R^(d2)                    are as defined infra, or                -    a —OP(═O)(OR^(f))₂ group, in which R^(f) is as                    defined infra;        -   Or            -   an —NR^(d1)R^(d2) group, as defined infra, with the                provisos that:                -   when one of R^(d1) and R^(d2) is H, then the other                    of R^(d1) and R^(d2) is neither H nor C₁-C₆-alkyl,                    and                -   R^(d1) and R^(d2) cannot simultaneously be                    C₁-C₆-alkyl        -   or            -   an —NR^(a)S(═O)₂R^(b) group, as defined infra, with the                proviso that:                -   when R_(a) is H, then R_(b) is not C₁-C₆-alkyl;        -   or            -   an —S(═O)₂R^(b) group, in which R^(b) is as defined                infra, with the provisos that when R^(b) is                —NR^(d1)R^(d2):                -   R^(d1) and R^(d2) are not both H,                -   when R^(d1) is H, then R^(d2) is not C₁-C₆-alkyl,                -   R^(d1) and R^(d2) are not both C₁-C₆-alkyl,        -   or            -   a —C(═O)R^(b) group, in which R^(b) is as defined infra;    -   or    -   b) an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group,        said aryl, heteroaryl, cycloalkyl or heterocycloalkyl group        being substituted with one or more —(CH₂)_(o)R¹⁴ groups, in each        occurrence of said —(CH₂)_(o)R¹⁴ group:        -   o is an integer of 1 or 2; and        -   R¹⁴ is as defined infra;    -   or    -   c) a C₂-C₁₀-alkenyl or C₅-C₁₀-cycloalkenyl group, said        C₂-C₁₀-alkenyl or C₅-C₁₀-cycloalkenyl group being optionally        substituted with one or more —(CH₂)_(o)R¹⁴ groups, in which o        and R¹⁴ are as defined infra;-   R⁷ and R⁸ are independently a hydrogen atom, a —N(R¹²)(R¹³), —OH,    —C₁-C₆-alkoxy, —C₁-C₆-alkyl, —CF₃,    —O—(CH₂)_(o)—(CH(OR¹¹))—(CH₂)_(m)—R⁹, —O—(CH₂)_(n)-cycloalkyl, aryl,    heteroaryl, cycloalkyl or heterocycloalkyl group, in which aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of    each other, optionally substituted with one or more halogen atoms,    C₁-C₆-alkyl or C₁-C₆-alkoxy groups;-   R⁹ and R¹⁰ are independently —OH, —C₁-C₆-alkoxy, halogen,    heteroaryl, —NR^(d1)R^(d2) or —N(R¹²)(R¹³);-   R¹¹, R¹² and R¹³:    -   are independently a hydrogen atom, a C₁-C₆-alkyl, aryl,        heteroaryl, cycloalkyl or heterocycloalkyl group, in which        C₁-C₆-alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl        are, independently of each other, optionally substituted with        one or more —(CH₂)_(o)R¹⁴ groups,-   or-   R¹² and R¹³, together with the N atom to which they are bound, form    a 5-, 6-, or 7-membered heterocyclic ring which optionally comprises    one or more additional heteroatoms, which optionally comprises one    or more —C(═O)— or —S(═O)₂ groups, and which is optionally    substituted with one or more —(CH₂)_(o)R¹⁴ groups;-   R¹⁴ is, in each occurrence, independently, a halogen atom, a    C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxyalkyl, cycloalkyl,    heterocycloalkyl, —OR^(c), —NR^(d1)R^(d2), —CN, —NHS(═O)₂H,    —NR^(a)S(═O)₂R^(b), —S(═O)₂R^(b) or —C(═O)R^(b) group;-   R¹⁵ is, in each occurrence, independently, a hydrogen atom or a    C₁-C₆-alkyl group, in which at least one R¹⁵ groups is C₁-C₆-alkyl;-   n is, in each occurrence, independently, an integer of 0, 1, 2, 3,    or 4;-   m is, in each occurrence, independently, an integer of 0, 1, or 2;    and-   o is, in each occurrence, independently, an integer of 0, 1, or 2;-   R^(a) is, in each occurrence, independently, a hydrogen atom or a    C₁-C₆-alkyl group;-   R^(b) is, in each occurrence, independently, an —OH, —OR^(c),    —SR^(c), —NR^(d1)R^(d2), a C₁-C₆-alkyl, aryl, heteroaryl, cycloalkyl    or heterocycloalkyl group, in which C₁-C₆-alkyl, heteroaryl,    cycloalkyl and heterocycloalkyl are, independently of each other,    optionally substituted one or more times with a halogen atom, an    —OH, C1-C6-alkyl or C₁-C₆-alkoxy group;-   R^(c) is, in each occurrence, independently, a hydrogen atom, a    —C(═O)R^(e), —S(═O)₂R^(e), C₁-C₆-alkyl, C₁-C₆-haloalkyl cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl group, in which C₁-C₆-alkyl,    C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,    are, independently of each other, optionally substituted one or more    times with a halogen atom, an —OH, aryl, —OR^(f), —NR^(d1)R^(d2), or    —OP(═O)(OR^(f))₂ group;-   R^(d1), R^(d2), R^(d1), R^(d2):    -   are, in each occurrence, independently of each other, a hydrogen        atom, a C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, —C(═O)R^(e), —S(═O)₂R^(e), or —C(═O)NR^(g1)R^(g2)        group, in which C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl are, independently of each other, optionally        substituted one or more times, the same way or differently, with        a halogen atom, a C₁-C₆-alkyl, an —OH or aryl, —NR^(g1)R^(g2),        —OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or —OP(═O)(OR^(f))₂ group;-   or-   R^(d1) and R^(d2), together with the nitrogen atom to which they are    bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered    heterocycloalkyl ring, which is optionally substituted one or more    times, the same way or differently, with a halogen atom, a    C₁-C₆-alkyl, —NR^(g1)R^(g2), —OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or    —OP(═O)(OR^(f))₂ group; and the carbon backbone of which is    optionally interrupted one or more times, in the same way or    differently, with NH, NR^(d3), O, or S, and is optionally    interrupted one or more times, in the same way or differently, with    a —C(═O)—, —S(═O)—, and/or —S(═O)₂— group, and optionally contains    one or more double bonds;-   R^(d3) is a hydrogen atom, a C₁-C₆-alkyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl group, in which C₁-C₆-alkyl or    cycloalkyl are, independently of each other, optionally substituted    one or more times with a halogen atom, an —OH, C₁-C₆-alkyl,    cycloalkyl, C₁-C₆-haloalkyl or C₁-C₆-alkoxy group;-   R^(e) is an —NR^(g1)R^(g2), C₁-C₆-alkyl, cycloalkyl, C₁-C₆-alkoxy,    aryl or heteroaryl group;-   R^(f) is a hydrogen atom, a —C(═O)R^(e), C₁-C₆-alkyl,    C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl    group, in which C₁-C₆-alkyl, C₁-C₆-haloalkyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl are, independently of each    other, optionally substituted one or more times with a halogen atom,    an —OH, C₁-C₆-alkoxy, aryl, or —NR^(g1)R^(g2) group;-   R^(g1)R^(g2) are, independently of each other, a hydrogen atom, a    C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl    group; or-   R^(g1) and R^(g2) together with the nitrogen atom to which they are    bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered    heterocycloalkyl ring, which is optionally substituted one or more    times, in the same way or differently, with a halogen atom, an —OH,    C₁-C₆-alkyl, C₁-C₆-alkoxy group; and the carbon backbone of which is    optionally interrupted one or more times, in the same way or    differently, with NH, NR^(a), O, S, and is optionally interrupted    one or more times, in the same way or differently, with a —C(═O)—,    —S(═O)—, and/or —S(═O)₂— group, and optionally contains one or more    double bonds;-   with the proviso that:-   X—R⁶ is not (O or NH)—(CH₂)_(r)—R^(r),    -   where R^(r) is NR^(s1)R^(s2) in which    -   r=1-4, and    -   R^(s1), R^(s2)=independently hydrogen, C₁-C₈ alkyl, or taken        together with the nitrogen to which they are attached, form a        3-10 member cyclic ring optionally containing one oxygen atom or        one sulfur atom or one NH or N—C₁-C₈ alkyl group;-   or a tautomer, stereoisomer, physiologically acceptable salt,    hydrate, solvate, metabolite, or prodrug thereof.

In accordance with a further particular embodiment, the presentinvention relates to compounds of general formula (I):

-   R¹ and R² are the same or different and are independently a halogen    atom, a methyl, or C₂-alkynyl group, in which at least one of R¹ and    R² is a halogen atom;-   R³ is, in each occurrence, a halogen atom;-   q is an integer of 1, 2, or 3;-   R⁴ is a hydrogen atom;-   R⁵ is a —C(═O)NH₂ group;-   X is —O—;-   R⁶ is —(CH₂)_(n)—Y;-   Y is an aryl or heteroaryl group, said aryl or heteroaryl group    being substituted with a —(CH₂)_(o)Y′ group, in each occurrence of    said —(CH₂)_(o)Y′ group:    -   o is an integer of 0; and    -   Y′ is, independently:        -   an —NR^(d1)R^(d2) group, as defined infra, with the provisos            that:            -   when one of R^(d1) and R^(d2) is H, then the other of                R^(d1) and R^(d2) is neither H nor C₁-C₆-alkyl, and            -   R^(d1) and R^(d2) cannot simultaneously be C₁-C₆-alkyl;    -   or        -   an —NR^(a)S(═O)₂R^(b) group, as defined infra, with the            proviso that:            -   when R_(a) is H, then R_(b) is not C₁-C₆-alkyl;-   R⁷ and R⁸ are independently a hydrogen atom, a —N(R¹²)(R¹³), —OH,    —C₁-C₆-alkoxy, —C₁-C₆-alkyl, —CF₃,    —O—(CH₂)_(n)—(CH(OR¹¹))—(CH₂)_(m)—R⁹, —O—(CH₂)_(n)-cycloalkyl, aryl,    heteroaryl, cycloalkyl or heterocycloalkyl group, in which aryl,    heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of    each other, optionally substituted with one or more halogen atoms,    C₁-C₆-alkyl or C₁-C₆-alkoxy groups;-   R⁹ and R¹⁰ are independently —OH, —C₁-C₆-alkoxy, halogen,    heteroaryl, —NR^(d1)R^(d2) or —N(R¹²)(R¹³);-   R¹¹, R¹² and R¹³:    -   are independently a hydrogen atom, a C₁-C₆-alkyl, aryl,        heteroaryl, cycloalkyl or heterocycloalkyl group, in which        C₁-C₆-alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl        are, independently of each other, optionally substituted with        one or more —(CH₂)_(o)R¹⁴ groups,-   or-   R¹² and R¹³, together with the N atom to which they are bound, form    a 5-, 6-, or 7-membered heterocyclic ring which optionally comprises    one or more additional heteroatoms, which optionally comprises one    or more —C(═O)— or —S(═O)₂ groups, and which is optionally    substituted with one or more —(CH₂)_(o)R¹⁴ groups;-   R¹⁴ is, in each occurrence, independently, a halogen atom, a    C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxyalkyl, cycloalkyl,    heterocycloalkyl, —OR^(c), —NR^(d1)R^(d2), —CN, —NHS(═O)₂H,    —NR^(a)S(═O)₂R^(b), —S(═O)₂R^(b) or —C(═O)R^(b) group;-   R¹⁵ is, in each occurrence, independently, a hydrogen atom or a    C₁-C₆-alkyl group, in which at least one R¹⁵ groups is C₁-C₆-alkyl;-   n is, in each occurrence, independently, an integer of 0, 1, 2, 3,    or 4;-   m is, in each occurrence, independently, an integer of 0, 1, or 2;    and-   o is, in each occurrence, independently, an integer of 0, 1, or 2;-   R^(a) is, in each occurrence, independently, a hydrogen atom or a    C₁-C₆-alkyl group;-   R^(b) is, in each occurrence, independently, an —OH, —OR^(c),    —SR^(c), —NR^(d1)R^(d2), a C₁-C₆-alkyl, aryl, heteroaryl, cycloalkyl    or heterocycloalkyl group, in which C₁-C₆-alkyl, heteroaryl,    cycloalkyl and heterocycloalkyl are, independently of each other,    optionally substituted one or more times with a halogen atom, an    —OH, C₁-C₆-alkyl or C₁-C₆-alkoxy group;-   R^(c) is, in each occurrence, independently, a hydrogen atom, a    —C(═O)R^(e), —S(═O)₂R^(e), C₁-C₆-alkyl, C₁-C₆-haloalkyl cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl group, in which C₁-C₆-alkyl,    C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl,    are, independently of each other, optionally substituted one or more    times with a halogen atom, an —OH, aryl, —OR^(f), —NR^(d1)R^(d2), or    —OP(═O)(OR^(f))₂ group;-   R^(d1), R^(d2), R^(d1), R^(d2):    -   are, in each occurrence, independently of each other, a hydrogen        atom, a C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, —C(═O)R^(e), —S(═O)₂R^(e), or —C(═O)NR^(g1)R^(g2)        group, in which C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl,        or heteroaryl are, independently of each other, optionally        substituted one or more times, the same way or differently, with        a halogen atom, a C₁-C₆-alkyl, an —OH or aryl, —NR^(g1)R^(g2),        —OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or —OP(═O)(OR^(f))₂ group;-   or-   R^(d1) and R^(d2), together with the nitrogen atom to which they are    bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered    heterocycloalkyl ring, which is optionally substituted one or more    times, the same way or differently, with a halogen atom, a    C₁-C₆-alkyl, —NR^(g1)R^(g2), —OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or    —OP(═O)(OR^(f))₂ group; and the carbon backbone of which is    optionally interrupted one or more times, in the same way or    differently, with NH, NR^(d3), O, or S, and is optionally    interrupted one or more times, in the same way or differently, with    a —C(═O)—, —S(═O)—, and/or —S(═O)₂— group, and optionally contains    one or more double bonds;-   R^(d3) is a hydrogen atom, a C₁-C₆-alkyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl group, in which C₁-C₆-alkyl or    cycloalkyl are, independently of each other, optionally substituted    one or more times with a halogen atom, an —OH, C₁-C₆-alkyl,    cycloalkyl, C₁-C₆-haloalkyl or C₁-C₆-alkoxy group;-   R^(e) is an —NR^(g1)R^(g2), C₁-C₆-alkyl, cycloalkyl, C₁-C₆-alkoxy,    aryl or heteroaryl group;-   R^(f) is a hydrogen atom, a —C(═O)R^(e), C₁-C₆-alkyl,    C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl    group, in which C₁-C₆-alkyl, C₁-C₆-haloalkyl, cycloalkyl,    heterocycloalkyl, aryl, or heteroaryl are, independently of each    other, optionally substituted one or more times with a halogen atom,    an —OH, C₁-C₆-alkoxy, aryl, or —NR^(g1)R^(g2) group;-   R^(g1), R^(g2) are, independently of each other, a hydrogen atom, a    C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl    group; or-   R^(g1) and R^(g2) together with the nitrogen atom to which they are    bound, form a 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered    heterocycloalkyl ring, which is optionally substituted one or more    times, in the same way or differently, with a halogen atom, an —OH,    C₁-C₆-alkyl, C₁-C₆-alkoxy group; and the carbon backbone of which is    optionally interrupted one or more times, in the same way or    differently, with NH, NR^(a), O, S, and is optionally interrupted    one or more times, in the same way or differently, with a —C(═O)—,    —S(═O)—, and/or —S(═O)₂— group, and optionally contains one or more    double bonds;-   with the proviso that:-   X—R⁶ is not (O or NH)—(CH₂)_(r)—R^(r),    -   where R^(r) is NR^(s1)R^(s2) in which-   r=1-4, and-   R^(s1), R^(s2)=independently hydrogen, C₁-C₈ alkyl, or taken    together with the nitrogen to which they are attached, form a 3-10    member cyclic ring optionally containing one oxygen atom or one    sulfur atom or one NH or N—C₁-C₈ alkyl group;-   or a tautomer, stereoisomer, physiologically acceptable salt,    hydrate, solvate, metabolite, or prodrug thereof.

It is to be understood that the present invention relates to anysub-combination within any embodiment of the present invention ofcompounds of general formula (I), supra.

More particularly still, the present invention covers compounds ofgeneral formula (I) which are disclosed in the Example section of thistext, infra.

DEFINITIONS

The term “alkyl” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containingsolely carbon and hydrogen atoms, containing no unsaturation, havingfrom one to eight carbon atoms, and which is attached to the rest of themolecule by a single bond, such as illustratively, methyl, ethyl,n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and1,1-dimethylethyl (t-butyl).

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched orbranched chain having about 2 to about 10 carbon atoms, e.g., ethenyl,1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, 2- and butenyl.

The term “alkynyl” refers to a straight or branched chain hydrocarbonylradicals having at least one carbon-carbon triple bond, and having inthe range of about 2 up to 12 carbon atoms (with radicals having in therange of about 2 up to 10 carbon atoms presently being preferred) e.g.,ethynyl.

The term “alkoxy” denotes an alkyl group as defined herein attached viaoxygen linkage to the rest of the molecule. Representative examples ofthose groups are methoxy and ethoxy.

The term “alkoxyalkyl” denotes an alkoxy group as defined hereinattached via oxygen linkage to an alkyl group which is then attached tothe main structure at any carbon from alkyl group that results in thecreation of a stable structure at the rest of the molecule.Representative examples of those groups are —CH₂OCH₃, and —CH₂OC₂H₅.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and examples of multicyclic cycloalkyl groupsinclude perhydronaphthyl, adamantyl and norbornyl groups bridged to acyclic group or sprirobicyclic groups e.g. Spiro (4,4) non-2-yl. Theterm “cycloalkyl” is to be understood as preferably meaning a C₃-C₁₂cycloalkyl group, more particularly a saturated cycloalkyl group of theindicated ring size, meaning e.g. a cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, orcyclodecyl group; and also as meaning an unsaturated cycloalkyl groupcontaining one or more double bonds in the C-backbone, e.g. a C₃-C₁₀cycloalkenyl group, such as, for example, a cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,or cyclodecenyl group, wherein the linkage of said cyclolalkyl group tothe rest of the molecule can be provided to the double or single bond;and also as meaning such a saturated or unsaturated cycloalkyl groupbeing optionally substituted one or more times, independently of eachother, with a C₁-C₆ alkyl group and/or a halogen and/or an OR^(f) groupand/or a NR^(g1)R^(g2) group; such as, for example, a2-methyl-cyclopropyl group, a 2,2-dimethylcyclopropyl group, a2,2-dimethylcyclobutyl group, a 3-hydroxycyclopentyl group, a3-hydroxycyclohexyl group, a 3-dimethylaminocyclobutyl group, a3-dimethylaminocyclopentyl group or a 4-dimethylaminocyclohexyl group.

The term “cycloalkylalkyl” refers to cyclic ring-containing radicalscontaining in the range of about 3 up to 8 carbon atoms directlyattached to the alkyl group which is then also attached to the mainstructure at any carbon from the alkyl group that results in thecreation of a stable structure such as cyclopropylmethyl,cyclobutylethyl, and cyclopentylethyl.

The term “aryl” refers to aromatic radicals having in the range of 6 upto 14 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl,indanyl, biphenyl being optionally further substituted by an C₁-C₆ alkylgroup and/or a halogen atom.

The term “arylalkyl” refers to an aryl group as defined herein directlybonded to an alkyl group as defined herein which is then attached to themain structure at any carbon from alkyl group that results in thecreation of a stable structure at the rest of the molecule. e.g.,—CH₂C₆H₅, —C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a stable 3- to 15 membered ringradical which consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclic ring radicalmay be a monocyclic, bicyclic or tricyclic ring system, which mayinclude fused, bridged or spiro ring systems, and the nitrogen,phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ringradical is optionally oxidized to various oxidation states. In addition,the nitrogen atom is optionally quaternized; and the ring radical may bepartially or fully saturated (i.e., heteroaromatic or heteroarylaromatic). Examples of such heterocyclic ring radicals include, but arenot limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazil, pyridyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl,tetrahydroisoindolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl,isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl,indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl,quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl,thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl,tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl.

The term “heterocycloalkyl” is to be understood as preferably meaning aC₃-C₁₀ cycloalkyl group, as defined supra, featuring the indicatednumber of ring atoms, wherein one or more ring atom(s) is (are) (a)heteroatom(s) such as NH, NR^(d3), O, S, or (a) group(s) such as a C(O),S(O), S(O)₂, or, otherwise stated, in a C_(n)-cycloalkyl group, (wherein_(n) is an integer of 3, 4, 5, 6, 7, 8, 9, or 10), one or more carbonatom(s) is (are) replaced by said heteroatom(s) or said group(s) to givesuch a C_(n) cycloheteroalkyl group; and also as meaning an unsaturatedheterocycloalkyl group containing one or more double bonds in theC-backbone, wherein the linkage of said heterocyclolalkyl group to therest of the molecule can be provided to the double or single bond; andalso as meaning such a saturated or unsaturated heterocycloalkyl groupbeing optionally substituted one or more times, independently of eachother, with a C₁-C₆ alkyl group and/or a halogen and/or an OR^(f) groupand/or a NR^(g1)R^(g2) group. Thus, said C_(n) cycloheteroalkyl grouprefers, for example, to a three-membered heterocycloalkyl, expressed asC₃-heterocycloalkyl, such as oxiranyl (C₃). Other examples ofheterocycloalkyls are oxetanyl (C₄), aziridinyl (C₃), azetidinyl (C₄),tetrahydrofuranyl (C₅), pyrrolidinyl (C₅), morpholinyl (C₆), dithianyl(C₆), thiomorpholinyl (C₆), piperidinyl (C₆), tetrahydropyranyl (C₆),piperazinyl (C₆), trithianyl (C₆), homomorpholinyl (C₇), homopiperazinyl(C₇) and chinuclidinyl (C₈); said cycloheteroalkyl group refers also to,for example, 4-methylpiperazinyl, 3-methyl-4-methylpiperazine,3-fluoro-4-methylpiperazine, 4-dimethylaminopiperidinyl,4-methylaminopiperidinyl, 4-aminopiperidinyl,3-dimethylaminopiperidinyl, 3-methylaminopiperidinyl,3-aminopiperidinyl, 4-hydroxypiperidinyl, 3-hydroxypiperidinyl,2-hydroxypiperidinyl, 4-methylpiperidinyl, 3-methylpiperidinyl,3-dimethylaminopyrrolidinyl, 3-methylaminopyrrolidinyl,3-aminopyrrolidinyl or methylmorpholinyl.

The term “heteroaryl” refers to a heterocyclic ring radical as definedherein which is aromatic being optionally further substituted by anC₁-C₆ alkyl group and/or a halogen atom. The heteroaryl ring radical maybe attached to the main structure at any heteroatom or carbon atom thatresults in the creation of a stable structure.

The heterocyclic ring radical may be attached to the main structure atany heteroatom or carbon atom that results in the creation of a stablestructure.

The term “heteroarylalkyl” refers to heteroaryl ring radical as definedherein directly bonded to alkyl group. The heteroarylalkyl radical maybe attached to the main structure at any carbon atom from the alkylgroup that results in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedherein. The heterocyclyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocyclic ring radical asdefined herein directly bonded to alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure.

The term “carbonyl” refers to an oxygen atom bound to a carbon atom ofthe molecule by a double bond.

The term “halogen” refers to radicals of fluorine, chlorine, bromine andiodine.

As used herein, the term “one or more times”, e.g. in the definition ofthe substituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or fivetimes, particularly one, two, three or four times, more particularlyone, two or three times, even more particularly one or two times”.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

The compounds of this invention may contain one or more asymmetriccenters, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms may be present in the (R)or (S) configuration, resulting in racemic mixtures in the case of asingle asymmetric center, and diastereomeric mixtures in the case ofmultiple asymmetric centers. In certain instances, asymmetry may also bepresent due to restricted rotation about a given bond, for example, thecentral bond adjoining two substituted aromatic rings of the specifiedcompounds.

Substituents on a ring may also be present in either cis or trans form.It is intended that all such configurations (including enantiomers anddiastereomers), are included within the scope of the present invention.Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthis invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallization. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivitization, optimally chosen to maximize the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDiacel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivitization, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as pharmaceutically acceptable salts,co-precipitates, metabolites, hydrates, solvates and prodrugs of all thecompounds of examples. The term “pharmaceutically acceptable salt”refers to a relatively non-toxic, inorganic or organic acid additionsalt of a compound of the present invention. For example, see S. M.Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19.Pharmaceutically acceptable salts include those obtained by reacting themain compound, functioning as a base, with an inorganic or organic acidto form a salt, for example, salts of hydrochloric acid, sulfuric acid,phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalicacid, maleic acid, succinic acid and citric acid. Pharmaceuticallyacceptable salts also include those in which the main compound functionsas an acid and is reacted with an appropriate base to form, e.g.,sodium, potassium, calcium, magnesium, ammonium, and chorine salts.Those skilled in the art will further recognize that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

Representative salts of the compounds of this invention include theconventional non-toxic salts and the quaternary ammonium salts which areformed, for example, from inorganic or organic acids or bases by meanswell known in the art. For example, such acid addition salts includeacetate, adipate, alginate, ascorbate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, itaconate, lactate,maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate,tartrate, thiocyanate, tosylate, and undecanoate.

Base salts include alkali metal salts such as potassium and sodiumsalts, alkaline earth metal salts such as calcium and magnesium salts,and ammonium salts with organic bases such as dicyclohexylamine andN-methyl-D-glutamine. Additionally, basic nitrogen containing groups maybe quaternized with such agents as lower alkyl halides such as methyl,ethyl, propyl, and butyl chlorides, bromides and iodides; dialkylsulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

A solvate for the purpose of this invention is a complex of a solventand a compound of the invention in the solid state. Exemplary solvateswould include, but are not limited to, complexes of a compound of theinvention with ethanol or methanol. Hydrates are a specific form ofsolvate wherein the solvent is water.

Method(s) of Making the Compounds of the Invention General PreparativeMethods

The particular process to be utilized in the preparation of thecompounds used in this embodiment of the invention depends upon thespecific compound desired. Such factors as the selection of the specificsubstituents play a role in the path to be followed in the preparationof the specific compounds of this invention. Those factors are readilyrecognized by one of ordinary skill in the art.

The compounds of the invention may be prepared by use of known chemicalreactions and procedures. Nevertheless, the following generalpreparative methods are presented to aid the reader in synthesizing thecompounds of the present invention, with more detailed particularexamples being presented below in the experimental section describingthe working examples.

The compounds of the invention can be made according to conventionalchemical methods, and/or as disclosed below, from starting materialswhich are either commercially available or producible according toroutine, conventional chemical methods. General methods for thepreparation of the compounds are given below, and the preparation ofrepresentative compounds is specifically illustrated in examples.

Synthetic transformations that may be employed in the synthesis ofcompounds of this invention and in the synthesis of intermediatesinvolved in the synthesis of compounds of this invention are known by oraccessible to one skilled in the art. Collections of synthetictransformations may be found in compilations, such as:

-   J. March. Advanced Organic Chemistry, 4th ed.; John Wiley: New York    (1992)-   R. C. Larock. Comprehensive Organic Transformations, 2nd ed.;    Wiley-VCH: New York (1999)-   F. A. Carey; R. J. Sundberg. Advanced Organic Chemistry, 2nd ed.;    Plenum Press: New York (1984)-   T. W. Greene; P. G. M. Wuts. Protective Groups in Organic Synthesis,    3rd ed.; John Wiley: New York (1999)-   L. S. Hegedus. Transition Metals in the Synthesis of Complex Organic    Molecules, 2nd ed.; University Science Books: Mill Valley, Calif.    (1994)-   L. A. Paquette, Ed. The Encyclopedia of Reagents for Organic    Synthesis; John Wiley: New York (1994)-   A. R. Katritzky; O. Meth-Cohn; C. W. Rees, Eds. Comprehensive    Organic Functional Group Transformations; Pergamon Press: Oxford, UK    (1995)-   G. Wilkinson; F. G A. Stone; E. W. Abel, Eds. Comprehensive    Organometallic Chemistry; Pergamon Press: Oxford, UK (1982)-   B. M. Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon    Press: Oxford, UK (1991)-   A. R. Katritzky; C. W. Rees Eds. Comprehensive Heterocylic    Chemistry; Pergamon Press: Oxford, UK (1984)-   A. R. Katritzky; C. W. Rees; E. F. V. Scriven, Eds. Comprehensive    Heterocylic Chemistry II; Pergamon Press: Oxford, UK (1996)-   C. Hansch; P. G. Sammes; J. B. Taylor, Eds. Comprehensive Medicinal    Chemistry: Pergamon Press: Oxford, UK (1990).

In addition, recurring reviews of synthetic methodology and relatedtopics include Organic Reactions; John Wiley: New York; OrganicSynthesis; John Wiley: New York; Reagents for Organic Synthesis: JohnWiley: New York; The Total Synthesis of Natural Products; John Wiley:New York; The Organic Chemistry of Drug Synthesis; John Wiley New York;Annual Reports in Organic Synthesis; Academic Press: San Diego Calif.;and Methoden der Organischen Chemie (Houben-Weyl); Thieme: Stuttgart,Germany. Furthermore, databases of synthetic transformations includeChemical Abstracts, which may be searched using either CAS OnLine orSciFinder, Handbuch der Organischen Chemie (Beilstein), which may besearched using SpotFire, and REACCS.

Reaction Schemes:

The following schemes illustrate general synthetic routes to thecompounds of general formula (I) of the invention and are not intendedto be limiting. It needs to be understood that transformationsgenerically described in the following paragraphs may be performed atdifferent reaction temperatures and in different solvents dependingupon, for example, the reactivity of reagents and their respectivesolubility charactersitics. More specifically, certain transformationsmay require heating in a solvent of a suitable boiling point. Inspecific cases heating of reaction mixtures may be achieved by using amicrowave oven. In certain cases additives such as, for example, bases,phase transfer catalysts or ionic liquids may be used to modify reactionconditions to improve reaction turnover oder heating characteristics. Itis obvious to the person skilled in the art that the order oftransformations as exemplified in Schemes 1 to 8 can be modified invarious ways. The order of transformations exemplified in Schemes 1 to 8is therefore not intended to be limiting. In addition, interconversionof substituents, for example of residues R¹, R², R³, R⁵, R⁶, R^(6a), R⁷or R^(a) can be achieved before and/or after the exemplifiedtransformations. These modifications can be such as the introduction ofprotecting groups, cleavage of protecting groups, reduction or oxidationof functional groups, halogenation, metallation, substitution or otherreactions known to the person skilled in the art. These transformationsinclude those which introduce a functionality which allows for furtherinterconversion of substituents. Appropriate protecting groups and theirintroduction and cleavage are well-known to the person skilled in theart (see for example T. W. Greene and P. G. M. Wuts in Protective Groupsin Organic Synthesis, 3^(rd) edition, Wiley 1999).

Reaction Scheme 1 illustrates one general method for the preparation ofthe Formula (I) compounds. A 2,6-difluorophenyl derivative of Formula(II) carrying an electron-withdrawing R⁵ substituent is reacted with ananiline of Formula (III) and base to form the amine intermediate ofFormula (IV). This intermediate is reacted with an alcohol R^(6a)OH[Formula (V) where X═O], a thiol R^(6a)SH [Formula (V) where X═S], or anamine R^(6a)NH₂ [Formula (V) where X═NH] to form a product of Formula(Ia). This compound is optionally liberated from its protecting group(acetal or Boc) using an acid such as HCl or TFA to form the finalproduct of Formula (I).

Scheme 1 General procedure for the preparation of compounds of thegeneral Formula (I), wherein R¹, R², R³, R⁵, R⁶, X and q are as definedin the description and claims of this invention and R^(6a) stands for anoptionally protected form of a R⁶ group, for example, for a R⁶ groupcarrying a Boc-protection group or an acetal.

Reaction Scheme 2 illustrates a further general method for thepreparation of the Formula (I) compounds. A 2,6-difluorophenylderivative of Formula (II) carrying an is electron-withdrawing R⁵substituent is reacted in the presence of a base with an alcoholR^(6a)OH [Formula (V) where X═O], a thiol R^(6a)SH [Formula (V) whereX═S], or an amine R^(6a)NH₂ [Formula (V) where X═NH] to form anintermediate of Formula (VI). This intermediate is reacted with ananiline of Formula (III) in the presence of a base to form a product ofFormula (Ia). This compound is optionally liberated from its protectinggroup (e.g. acetal or Boc) using an acid, for example hydrochloric acidor TFA, to form the final product of Formula (I).

Scheme 2 General procedure for the preparation of compounds of thegeneral Formula (I), wherein R¹, R², R³, R⁵, R⁶, X and q are as definedin the description and claims of this invention and R^(5a) stands for anoptionally protected form of a R⁶ group, for example, for a R⁶ groupcarrying a Boc-protection group or an acetal.

Reaction Scheme 3 illustrates one further preferred general method forthe preparation of the formula (I) compounds. A 2,6-difluorophenylderivative of formula (II) carrying an electron-withdrawing R⁵substituent is reacted in the presence of a base with an aniline offormula (III) to form a product of formula (IV). Protection of theaniline functionality yields a product of formula (VII), in which PGrepresents a suitable protecting group such as, for example, atert-butoxycarbonyl (Boc) group, a benzyloxy carbonyl group orderivatives thereof or an acetyl group or derivatives thereof.Appropriate protecting group reagents and their introduction arewell-known to the person skilled in the art (see for example T. W.Greene and P. G. M. Wuts in Protective Groups in Organic Synthesis,3^(rd) edition, Wiley 1999). This product is subsequently reacted in thepresence of a base with a compound of formula (V) to form product(VIII). This compound is optionally liberated from its protecting groupsin a concerted or stepwise fashion using, for example, an acid, such as,for example, hydrochloric acid or TFA, or a base, such as, for example,sodium hydroxide, sodium ethanolate or lithium hydroxide, to form thefinal product of Formula (I). In a more specific application of thisgeneral method, the R⁵ group and the PG group in compounds of Formulae(VII) and (VIII) may form a 5- or 6-membered cycle. For example, in acase where the R⁵ group in Formula (IV) stands for a carboxylic acid,reaction with paraformaldehyde would lead to a benzoxazine which couldbe cleaved—after reaction with a R^(6a)XH group—by reaction with, forexample, polymer bound glycerol and hydrochloric acid thereby providinga compound of Formula (Ia), in which R⁵ would stand for a carboxylicacid.

Scheme 3 General procedure for the preparation of compounds of thegeneral Formula (I), wherein R¹, R², R³, R⁵, R⁶, X and q are as definedin the description and claims of this invention, R^(6a) stands for anoptionally protected form of a R⁶ group, for example, for a R⁶ groupcarrying a Boc-protection group or an acetal, and PG stands for asuitable protecting groups such as, for example, a Boc group or abenzyloxycarbonyl group or derivatives thereof or an acetate orderivatives thereof.

Reaction Scheme 4 illustrates a more specific method for the preparationof the Formula (Id) compounds [Formula (I) where R⁵═C(O)NH₂]. A nitriteof Formula (Ib) [Formula (Ia) where R⁵═CN], prepared as described inSchemes 1 to 3, is transformed into the corresponding amide derivativeof Formula Ic [Formula (Ia) where R⁵═C(O)NH₂]. Suitable conditions forthis transformation include, but are not limited to, is the treatmentwith hydrogen peroxide in the presence of a base. Compound (Ic) isoptionally liberated from its protecting group (acetal or Boc) using anacid such as HCl or TFA to form the final product of Formula (Id).

Scheme 4 More specific procedure for the preparation of compounds of thegeneral Formula (Id), wherein R¹, R², R³, R⁶, X and q are as defined inthe description and claims of this invention and R^(6a) stands for anoptionally protected form of a R⁶ group, for example, for a R⁶ groupcarrying a Boc-protection group or an acetal.

Reaction Scheme 5 illustrates a general method for the preparation ofthe Formula (Ig) compounds [Formula (I) where R²=ethinyl]. Anintermediate of Formula (Ie) [Formula (Ia) where R²=iodo], prepared asdescribed in Schemes 1 to 4, is reacted with ethine in the presence ofcatalytic amounts of a Pd catalyst such as PdCl₂(PPh₃)₂, catalyticamounts of copper iodide, in the presence of a solvent such as DMF toform is the corresponding alkyne derivative of Formula If [Formula (Ia)where R²=ethinyl]. Alternatively, mono-trialkylsilyl-protected acetylenesuch as for example, trimethylsilyl (TMS) acetylene, may be employed ina Sonogashira-type coupling under conditions as described above followedby cleavage of the trialkylsilyl group by treatment with, for example,tetrabutylammonium fluoride or potassium carbonate in methanol.Alternatively, by using tetrabutylammonium fluoride as base in theSonogashira-type coupling, coupling of TMS acetylene and cleavage of theTMS-group can be achieved in a one pot transformation. Transitionmetal-catalyzed couplings of (hetero)aryl halides with alkynes andtrialkylsilyl alkynes are well known to the person skilled in the art(see for example (a) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107,874; (b) Negishi, E.-i., Anastasia, L. Chem. Rev. 2003, 103, 1979; seealso: (c) Eur. J. Org. Chem. 2005, 20, 4256; (d) J. Org. Chem. 2006, 71,2535 and references therein; (e) Chem. Commun. 2004, 17, 1934). Variouspalladium-catalyst/co-catalyst/ligand/base/solvent combinations havebeen published in the scientific literature which allow a fine-tuning ofthe required reaction conditions in order to allow for a broad set ofadditional functional groups on both coupling partners (see referencesin the above cited reviews). Additionally, recently developed proceduresemploying e.g. zinc acetylides, alkynyl magnesium salts or alkynyltrifluoroborate salts further broaden the scope of this process.Compound (If) is optionally liberated from its protecting group (acetalor Boc) using an acid such as HCl or TFA to form the final product ofFormula (Ig). Furthermore, the described procedures can be applied tofurther alkyne substrates, such as, for example, C1-C6 alkynes.

Scheme 5 General procedure for the preparation of compounds of thegeneral Formula (Ig) by coupling of an iodide of general formula (Ie) isreacted with a suitable alkyne to yield a compound of Formula (If),wherein R¹, R², R³, R⁵, R⁶, X and q are as defined in the descriptionand claims of this invention and R^(6a) stands for an optionallyprotected form of a R⁶ group, for example, for a R⁶ group carrying aBoc-protection group or an acetal.

Reaction Scheme 6 illustrates one general method for the preparation ofthe Formula (Ii) compounds [Formula (I) where R⁵═C(O)NHR⁷]. Anintermediate of Formula Ic [Formula (Ia) where R⁵═C(O)NH₂], prepared asdescribed in Schemes 1 to 5, is reacted with an alkylating reagent toform the corresponding N-alkyl amide derivative of Formula Ih [Formula(Ia) where R⁵═C(O)NHR⁷]. This compound is optionally liberated from itsprotecting group (acetal or Boc) using an acid such as HCl or TFA toform the final product of Formula (II).

Scheme 6 General procedure for the preparation of compounds of thegeneral Formula (II), wherein R¹, R², R³, R⁶, R⁷, X and q are as definedin the description and claims of this invention and R^(6a) stands for anoptionally protected form of a R⁶ group, for example, for a R⁶ groupcarrying a Boc-protection group or an acetal.

Reaction Scheme 7 illustrates the general method for the preparation ofthe Formula (In) compounds. An intermediate of Formula (Im), prepared asdescribed in Schemes 1 to 6, is reacted with a dihydroxylating agentsuch as, for example, osmiumtetroxide, optionally in the presence of apromoter such as, for example, DMAP and in a suitable solvent such as,for example, acetone, to form the corresponding bishydroxy derivative ofFormula (In) as final compound. Similarly, analogs of compounds ofFormula (Im), in which the double bond is further substituted with alkylgroups or part of a cycloalkenyl ring, can be applied to the describeddihydroxlation conditions leading to analogs of compounds of Formula(In), in which the oxygenated carbon atoms carry additional alkylgroups. Alternatively, asymmetric dihydroxylation conditions as known tothe person skilled in the art can be employed to achieve the generaltransformation shown in Scheme 7 in an enantioselective fashion.

Scheme 7 General procedure for the preparation of compounds of thegeneral

Formula (In), wherein R¹, R², R³, R⁵, X and q are as defined in thedescription and claims of this invention.

Reaction Scheme 8 illustrates one additional specific method for thepreparation of the Formula (It) compounds. An intermediate of Formula(Ir), prepared by procedures described above, is transformed into thecorresponding methansulfonate (mesylate) by reaction with, for example,methansulfonyl chloride, optionally in the presence of a base.Subsequently this mesylate of Formula (Ir) is reacted either in situ orafter isolation with an amine of general formula (IX) to afford acompound of Formula (It). Other ways of activating an alcohol for asubsequent nucleophilic substitution reaction are known to the personskilled in the art, such as, for example, transformation into apara-toluene sulfonate (tosylate) or a nitro-phenylsulfonate.

Scheme 8 General procedure for the preparation of compounds of thegeneral Formula (It), wherein R¹; R², R³, R⁵, R⁶, R⁷, X and q are asdefined in the description and claims of this invention.

Reaction Scheme 9 illustrates one additional specific method for thepreparation of the Formula (Iv) compounds. An intermediate of Formula(Iu), prepared by procedures described above, is reacted with anappropriate sulfonylchloride optionally in the presence of a suitablebase to yield compounds of Formula (Iv).

Scheme 9 General procedure for the preparation of compounds of thegeneral Formula (Iv), wherein R¹, R², R³, R⁵, X, R^(b) and q are asdefined in the description and claims of this invention.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilized to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike.

For oral administration, the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, lozenges,melts, powders, solutions, suspensions, or emulsions, and may beprepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatin typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatin,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, coloring agents, and flavoring agents such as peppermint, oil ofwintergreen, or cherry flavoring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of anaqueous suspension. They provide the active ingredient in admixture witha dispersing or wetting agent, a suspending agent and one or morepreservatives. Suitable dispersing or wetting agents and suspendingagents are exemplified by those already mentioned above. Additionalexcipients, for example those sweetening, flavoring and coloring agentsdescribed above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavoring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavoring and coloring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methycellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimize or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al, “Compendium of Excipients for ParenteralFormulations” PDA Journal of Pharmaceutical Science & Technology 1998,52(5), 238-311; Strickley, R. G “Parenteral Formulations of SmallMolecule Therapeutics Marketed in the United States (1999)-Part-1” PDAJournal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; andNema, S. et al, “Excipients and Their Use in Injectable Products” PDAJournal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)air displacement agents (examples include but are not limited tonitrogen and argon);antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)chelating agents (examples include but are not limited to edetatedisodium and edetic acid)colorants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);clarifying agents (examples include but are not limited to bentonite);emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)flavorants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);levigating agents (examples include but are not limited to mineral oiland glycerin);oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)plasticizers (examples include but are not limited to diethyl phthalateand glycerol);solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);tablet/capsule opaquants (examples include but are not limited totitanium dioxide); tablet polishing agents (examples include but are notlimited to carnuba wax and white wax);thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);tonicity agents (examples include but are not limited to dextrose andsodium chloride);viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);andwetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 minutes.

Lyophilized powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lypholized powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60minutes.

Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

50 mg/mL of the desired, water-insoluble compound of this invention5 mg/mL sodium carboxymethylcellulose4 mg/mL TWEEN 809 mg/mL sodium chloride9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis. This method comprises administering to amammal in need thereof, including a human, an amount of a compound ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof; etc. which iseffective to treat the disorder. Hyper-proliferative disorders includebut are not limited, e.g., psoriasis, keloids, and other hyperplasiasaffecting the skin, benign prostate hyperplasia (BPH), solid tumors,such as cancers of the breast, respiratory tract, brain, reproductiveorgans, digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, as well as neuroectodermal and pinealtumor.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumors of the female reproductive organsinclude, but are not limited to endometrial, cervical, ovarian, vaginal,and vulvar cancer, as well as sarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixedhepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Kinase Disorders

The present invention also provides methods for the treatment ofdisorders associated with aberrant mitogen extracellular kinaseactivity, including, but not limited to stroke, heart failure,hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cysticfibrosis, symptoms of xenograft rejections, septic shock or asthma.

Effective amounts of compounds of the present invention can be used totreat such disorders, including those diseases (e.g., cancer) mentionedin the Background section above. Nonetheless, such cancers and otherdiseases can be treated with compounds of the present invention,regardless of the mechanism of action and/or the relationship betweenthe kinase and the disorder.

The phrase “aberrant kinase activity” or “aberrant tyrosine kinaseactivity,” includes any abnormal expression or activity of the geneencoding the kinase or of the polypeptide it encodes. Examples of suchaberrant activity, include, but are not limited to, over-expression ofthe gene or polypeptide; gene amplification; mutations which produceconstitutively-active or hyperactive kinase activity; gene mutations,deletions, substitutions, additions, etc.

The present invention also provides for methods of inhibiting a kinaseactivity, especially of mitogen extracellular kinase, comprisingadministering an effective amount of a compound of the presentinvention, including salts, polymorphs, metabolites, hydrates, solvates,prodrugs (e.g.: esters) thereof, and diastereoisomeric forms thereof.Kinase activity can be inhibited in cells (e.g., in vitro), or in thecells of a mammalian subject, especially a human patient in need oftreatment.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity (Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638), age-related macular degeneration (AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855),neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumor enlargement and metastasis. Moreover, thegrowth of new blood and lymph vessels in a tumor provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Combination Therapies

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. For example, the compounds of this invention can becombined with known anti-hyper-proliferative or other indication agents,and the like, as well as with admixtures and combinations thereof. Otherindication agents include, but are not limited to, anti-angiogenicagents, mitotic inhibitors, alkylating agents, anti-metabolites,DNA-intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzyme inhibitors, toposisomerase inhibitors, biologicalresponse modifiers, or anti-hormones.

The additional pharmaceutical agent can be aldesleukin, alendronic acid,alfaferone, alitretinoin, allopurinol, aloprim, aloxi, altretamine,aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole,anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine,azathioprine, BCG or tice BCG, bestatin, betamethasone acetate,betamethasone sodium phosphate, bexarotene, bleomycin sulfate,broxuridine, bortezomib, busulfan, calcitonin, campath, capecitabine,carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil,cisplatin, cladribine, cladribine, clodronic acid, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, DaunoXome, decadron, decadronphosphate, delestrogen, denileukin diftitox, depo-medrol, deslorelin,dexrazoxane, diethylstilbestrol, diflucan, docetaxel, doxifluridine,doxorubicin, dronabinol, DW-166HC, eligard, elitek, ellence, emend,epirubicin, epoetin alfa, epogen, eptaplatin, ergamisol, estrace,estradiol, estramustine phosphate sodium, ethinyl estradiol, ethyol,etidronic acid, etopophos, etoposide, fadrozole, farston, filgrastim,finasteride, fligrastim, floxuridine, fluconazole, fludarabine,5-fluorodeoxyuridine monophosphate, 5-fluorouracil (5-FU),fluoxymesterone, flutamide, formestane, fosteabine, fotemustine,fulvestrant, gammagard, gemcitabine, gemtuzumab, gleevec, gliadel,goserelin, granisetron HCl, histrelin, hycamtin, hydrocortone,eyrthro-hydroxynonyladenine, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, interferon alpha, interferon-alpha 2, interferonalfa-2A, interferon alfa-2B, interferon alfa-n1, interferon alfa-n3,interferon beta, interferon gamma-1a, interleukin-2, intron A, iressa,irinotecan, kytril, lentinan sulphate, letrozole, leucovorin,leuprolide, leuprolide acetate, levamisole, levofolinic acid calciumsalt, Levothroid, Levoxyl, lomustine, lonidamine, marinol,mechlorethamine, mecobalamin, medroxyprogesterone acetate, megestrolacetate, melphalan, menest, 6-mercaptopurine, Mesna, methotrexate,metvix, miltefosine, minocycline, mitomycin C, mitotane, mitoxantrone,Modrenal, Myocet, nedaplatin, neulasta, neumega, neupogen, nilutamide,nolvadex, NSC-631570, OCT-43, octreotide, ondansetron HCl, orapred,oxaliplatin, paclitaxel, pediapred, pegaspargase, Pegasys, pentostatin,picibanil, pilocarpine HCl, pirarubicin, plicamycin, porfimer sodium,prednimustine, prednisolone, prednisone, premarin, procarbazine,procrit, raltitrexed, rebif, rhenium-186 etidronate, rituximab,roferon-A, romurtide, salagen, sandostatin, sargramostim, semustine,sizofuran, sobuzoxane, solu-medrol, sparfosic acid, stem-cell therapy,streptozocin, strontium-89 chloride, synthroid, tamoxifen, tamsulosin,tasonermin, tastolactone, taxotere, teceleukin, temozolomide,teniposide, testosterone propionate, testred, thioguanine, thiotepa,thyrotropin, tiludronic acid, topotecan, toremifene, tositumomab,trastuzumab, treosulfan, tretinoin, trexall, trimethylmelamine,trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine,valrubicin, vesnarinone, vinblastine, vincristine, vindesine,vinorelbine, virulizin, zinecard, zinostatin stimalamer, zofran,ABI-007, acolbifene, actimmune, affinitak, aminopterin, arzoxifene,asoprisnil, atamestane, atrasentan, sorafenib, avastin, CCl-779,CDC-501, celebrex, cetuximab, crisnatol, cyproterone acetate,decitabine, DN-101, doxorubicin-MTC, dSLIM, dutasteride, edotecarin,eflornithine, exatecan, fenretinide, histamine dihydrochloride,histrelin hydrogel implant, holmium-166 DOTMP, ibandronic acid,interferon gamma, intron-PEG, ixabepilone, keyhole limpet hemocyanin,L-651582, lanreotide, lasofoxifene, libra, lonafarnib, miproxifene,minodronate, MS-209, liposomal MTP-PE, MX-6, nafarelin, nemorubicin,neovastat, nolatrexed, oblimersen, onco-TCS, osidem, paclitaxelpolyglutamate, pamidronate disodium, PN-401, QS-21, quazepam, R-1549,raloxifene, ranpirnase, 13-cis-retinoic acid, satraplatin, seocalcitol,T-138067, tarceva, taxoprexin, thymosin alpha 1, tiazofurine,tipifarnib, tirapazamine, TLK-286, toremifene, TransMID-107R, valspodar,vapreotide, vatalanib, verteporfin, vinflunine, Z-100, zoledronic acidor combinations thereof.

Optional anti-hyper-proliferative agents which can be added to thecomposition include but are not limited to compounds listed on thecancer chemotherapy drug regimens in the 11^(th) Edition of the MerckIndex, (1996), which is hereby incorporated by reference, such asasparaginase, bleomycin, carboplatin, carmustine, chlorambucil,cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine,dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin,etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide,irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine,mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone,prednisone, procarbazine, raloxifen, streptozocin, tamoxifen,thioguanine, topotecan, vinblastine, vincristine, and vindesine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to thosecompounds acknowledged to be used in the treatment of neoplasticdiseases in Goodman and Gilman's The Pharmacological Basis ofTherapeutics (Ninth Edition), editor Molinoff et al., publ. byMcGraw-Hill, pages 1225-1287, (1996), which is hereby incorporated byreference, such as aminoglutethimide, L-asparaginase, azathioprine,5-azacytidine cladribine, busulfan, diethylstilbestrol,2′,2′-difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine,ethinyl estradiol, 5-fluorodeoxyuridine, 5-fluorodeoxyuridinemono-phosphate, fludarabine phosphate, fluoxymesterone, flutamide,hydroxyprogesterone caproate, idarubicin, interferon,medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane,paclitaxel, pentostatin, N-phosphonoacetyl-L-aspartate (PALA),plicamycin, semustine, teniposide, testosterone propionate, thiotepa,trimethyl-melamine, uridine, and vinorelbine.

Other anti-hyper-proliferative agents suitable for use with thecomposition of the invention include but are not limited to otheranti-cancer agents such as epothilone and its derivatives, irinotecan,raloxifen and topotecan.

The compounds of the invention may also be administered in combinationwith protein therapeutics. Such protein therapeutics suitable for thetreatment of cancer or other angiogenic disorders and for use with thecompositions of the invention include, but are not limited to, aninterferon (e.g., interferon.alpha., .beta., or .gamma.) supraagonisticmonoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin,anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab,trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1,bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab,rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35,MT-103, rinfabate, AS-1402, B43-genistein, L-19 basedradioimmunotherapeutics, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322,rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine,APC-8024, NGR-hTNF, rhH1.3, IGN-311, Endostatin, volociximab, PRO-1762,lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein,PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab,alpha-particle-emitting radioisotope-llinked lintuzumab, EM-1421,HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7,Javelin—prostate cancer, Javelin—melanoma, NY-ESO-1 vaccine, EGFvaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab,zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept,denosumab, vaccine, CTP-37, efungumab, or 131I-chTNT-1/B. Monoclonalantibodies useful as the protein therapeutic include, but are notlimited to, muromonab-CD3, abciximab, edrecolomab, daclizumab,gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab,efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab,daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,(2) provide for the administration of lesser amounts of the administeredchemo-therapeutic agents,(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,(5) provide for a higher response rate among treated patients,(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,(7) provide a longer time for tumor progression, and/or(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

Methods of Sensitizing Cells to Radiation

In a distinct embodiment of the present invention, a compound of thepresent invention may be used to sensitize a cell to radiation. That is,treatment of a cell with a compound of the present invention prior toradiation treatment of the cell renders the cell more susceptible to DNAdamage and cell death than the cell would be in the absence of anytreatment with a compound of the invention. In one aspect, the cell istreated with at least one compound of the invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the invention incombination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated one or morecompounds of the invention prior to the treatment of the cell to causeor induce cell death. In one aspect, after the cell is treated with oneor more compounds of the invention, the cell is treated with at leastone compound, or at least one method, or a combination thereof, in orderto cause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In one embodiment, a cell is killed by treating the cell with at leastone DNA damaging agent. That is, after treating a cell with one or morecompounds of the invention to sensitize the cell to cell death, the cellis treated with at least one DNA damaging agent to kill the cell. DNAdamaging agents useful in the present invention include, but are notlimited to, chemotherapeutic agents (e.g., cisplatinum), ionizingradiation (X-rays, ultraviolet radiation), carcinogenic agents, andmutagenic agents.

In another embodiment, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signaling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signaling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of the invention isadministered to a cell prior to the radiation or orther induction of DNAdamage in the cell. In another aspect of the invention, a compound ofthe invention is administered to a cell concomitantly with the radiationor orther induction of DNA damage in the cell. In yet another aspect ofthe invention, a compound of the invention is administered to a cellimmediately after radiation or orther induction of DNA damage in thecell has begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

In accordance with another aspect, the present invention covers a methodof preparing compounds of the present invention, the method comprisingthe steps as described herein.

EXPERIMENTAL DETAILS AND GENERAL PROCESSES Abbreviations and Acronyms

A comprehensive list of the abbreviations used by organic chemists ofordinary skill in the art appears in The ACS Style Guide (third edition)or the Guidelines for Authors for the Journal of Organic Chemistry. Theabbreviations contained in said lists, and all abbreviations utilized byorganic chemists of ordinary skill in the art are hereby incorporated byreference. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, Handbook of Chemistry and Physics, 67th Ed., 1986-87.

More specifically, when the following abbreviations are used throughoutthis disclosure, they have the following meanings:

Ac₂O acetic anhydrideACN acetonitrileAcO (or OAc) acetateanhyd anhydrousaq aqueousAr arylatm atmosphereATP adenosine triphosphateb.i.d. twice a dayBiotage silica gel chromatographic system, Biotage Inc.Bn benzylbp boiling pointBz benzoylBOC tert-butoxycarbonyln-BuOH n-butanolt-BuOH tert-butanolt-BuOK potassium tert-butoxidecalcd calculatedCbz carbobenzyloxyCDI carbonyl diimidazoleCD₃OD methanol-d₄Celite® diatomaceous earth filter agent, Celite Corp.Cl-MS chemical ionization mass spectroscopy¹³C NMR carbon-13 nuclear magnetic resonanceconc concentratedDCC dicyclohexylcarbodiimideDCE dichloroethaneDCM dichloromethanedec decompositionDIBAL diisobutylaluminum hydroxide

DMAP 4-(N,N-dimethylamino)pyidine

DME 1,2-dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethylsulfoxideDTT dithiothreitolE entgegen (configuration)e.g. for exampleEI electron impactELSD evaporative light scattering detectoreq equivalentERK extracellular signal-regulated kinaseESI electrospray ionisationES-MS electrospray mass spectroscopyet al. and othersEtOAc ethyl acetateEtOH ethanol (100%)EtSH ethanethiolEt₂O diethyl etherEt₃N triethylamineGC gas chromatographyGC-MS gas chromatography-mass spectroscopyh hour, hours¹H NMR proton nuclear magnetic resonanceHCl hydrochloric acidHEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHex hexaneHMPA hexamethylphosphoramideHMPT hexamethylphosphoric triamideHPLC high performance liquid chromatographyIC₅₀ drug concentration required for 50% inhibitioni.e. that isinsol insolubleIPA isopropylamineIR infraredJ coupling constant (NMR spectroscopy)LAH lithium aluminum hydrideLC liquid chromatographyLC-MS liquid chromatography-mass spectrometryLDA lithium diisopropylamideMAPK mitogen-activated protein kinaseMeCN acetonitrileMEK MAPK/ERK kinaseMHz megahertzmin minute, minutesμl microlitermL milliliterμM micromolarmp melting pointMS mass spectrum, mass spectrometryMs methanesulfonylm/z mass-to-charge ratio

NBS N-bromosuccinimide

nM nanomolarNMM 4-methylmorpholineobsd observedp pagePBS phosphate buffered salinepp pagesPdCl₂dppf [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(OAc)₂ palladium acetatepH negative logarithm of hydrogen ion concentrationpK negative logarithm of equilibrium constantpK_(a) negative logarithm of equilibrium constant for associationPS-DIEA polystyrene-bound diisopropylethylamineq quartet (nmr)qt quintet (nmr)R_(f) retention factor (TLC)RT retention time (HPLC)rt room temperatureTBAF tetra-n-butylammonium fluorideTBST tris buffered saline with tweenTEA triethylamineTHF tetrahydrofuranTFA trifluoroacetic acidTFFH fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphateTLC thin layer chromatographyTMAD N,N,N′,N′-tetramethylethylenediamineTMSCl trimethylsilyl chlorideTs p-toluenesulfonylv/v volume per volumew/v weight per volumew/w weight per weightZ zusammen (configuration)

The percentage yields reported in the following examples are based onthe starting component that was used in the lowest molar amount. Air andmoisture sensitive liquids and solutions were transferred via syringe orcannula, and introduced into reaction vessels through rubber septa.Commercial grade reagents and solvents were used without furtherpurification. The term “concentrated under reduced pressure” refers touse of a Buchi rotary evaporator at a minimum pressure of approximately15 mm of Hg. All temperatures are reported uncorrected in degreesCelsius (° C.). Thin layer chromatography (TLC) was performed onpre-coated glass-backed silica gel 60 A F-254 250 μm plates.

The structures of compounds of this invention were confirmed using oneor more of the following procedures.

NMR

NMR spectra were acquired for each compound and were consistent with thestructures shown.

Routine one-dimensional NMR spectroscopy was performed on 400 MHzVarian® Mercury-plus spectrometers. The samples were dissolved indeuterated solvents. Chemical shifts were recorded on the ppm scale andwere referenced to the appropriate solvent signals, such as 2.49 ppm forDMSO-d⁶, 1.93 ppm for CD₃CN, 3.30 ppm for CD₃OD, 5.32 ppm for CD₂Cl₂ and7.26 ppm for CDCl₃ for ¹H spectra.

GC/MS

Electron impact mass spectra (EI-MS) were obtained with a HewlettPackard 5973 mass spectrometer equipped Hewlett Packard 6890 GasChromatograph with a J & W HP-5 column (0.25 uM coating; 30 m×0.32 mm).The ion source was maintained at 250° C. and spectra were scanned from50-550 amu at 0.34 sec per scan.

LC/MS

Unless otherwise noted, all retention times are obtained from the LC/MSand correspond to the molecular ion. High pressure liquidchromatography-electrospray mass spectra (LC/MS) were obtained using aHewlett-Packard 1100 HPLC equipped with a quaternary pump, a variablewavelength detector set at 254 nm, a Waters Sunfire C18 column (2.1×30mm, 3.5 □m), a Gilson autosampler and a Finnigan LCQ ion trap massspectrometer with electrospray ionization. Spectra were scanned from120-1200 amu using a variable ion time according to the number of ionsin the source. The eluents were A: 2% acetonitrile in water with 0.02%TFA, and B: 2% water in acetonirile with 0.018% TFA. Gradient elutionfrom 10% B to 95% B over 3.5 minutes at a flow rate of 1.0 mL/min wasused with an initial hold of 0.5 minutes and a final hold at 95% B of0.5 minutes. Total run time was 6.5 minutes.

Preparative HPLC:

Preparative HPLC was carried out in reversed phase mode using a GilsonHPLC system equipped with two Gilson 322 pumps, a Gilson 215Autosampler, a Gilson diode array detector, and a C-18 column (e.g. YMCPro 20×150 mm, 120 A). Gradient elution was used with solvent A as waterwith 0.1% TFA, and solvent B as acetonitrile with 0.1% TFA. Followinginjection onto the column as a solution, the compound was typicallyeluted with a mixed solvent gradient, such as 10-90% Solvent B inSolvent A over 15 minutes with flow rate of 25 mL/min. The fraction(s)containing the desired product were collected by UV monitoring at 254 or220 nm.

Preparative MPLC:

Preparative medium pressure liquid chromatography (MPLC) was carried outby standard silica gel “flash chromatography” techniques (e.g., Still,W. C. et al. J. Org. Chem. 1978, 43, 2923-5), or by using silica gelcartridges and devices such as the Combiflash and Biotage Flash systems.A variety of eluting solvents were used, as described in theexperimental protocols.

In order that this invention may be better understood, the followingexamples are set forth. These examples are for the purpose ofillustration only, and are not to be construed as limiting the scope ofthe invention in any manner. All publications mentioned herein areincorporated by reference in their entirety.

General Procedures

In the subsequent paragraphs detailed general procedures for thesynthesis of key intermediates and compounds of the present inventionare described.

General Procedure 1a (GP 1a): Introduction of C6 Side Chain (ConditionsA)

The respective 6 fluoro benzene was dissolved in THF and an alcoholR^(6a)OH (1.01 eq.) [Formula (III) where X═O], a thiol R^(6a)SH (1.01eq.) [Formula (III) where X═S], or an amine R^(6a)NH₂ (1.01 eq.)[Formula (III) where X═NH] was added. The mixture was treated withsodium hydride (2.01 eq.) and stirred at rt for 48 h. The reactionmixture was poured onto ice water and extracted three times with ethylacetate. The combined organic layers were washed one time with brine,dried over sodium sulfate, filtered off and concentrated to afford thecrude product which was optionally further purified by flash columnchromatography, trituration or preparative HPLC purification.

General Procedure 1b (GP 1b): Introduction of C6 Side Chain (ConditionsB)

The respective 6 fluoro benzene was dissolved in DMF, caesium carbonate(1-4 eq.) was added and the mixture allowed to stir at RT for 30 Min.Then molecular sieves were added, followed by the addition of an alcoholR^(6a)OH (1.2 eq.) [Formula (III) where X═O], a thiol R^(6a)SH (1.2 eq.)[Formula (III) where X═S], or an amine R^(6a)NH₂ (1.2 eq.) [Formula(III) where X═NH] in DMF. The mixture was stirred in a sealed pressuretube for 2-48 h. Etyl methyl ketone was added and the mixture was washedwith half concentrated brine twice. The combined organic layers wereconcentrated to afford the crude product which was optionally furtherpurified by flash column chromatography, trituration or preparative HPLCpurification.

General Procedure 1c (GP 1c): Introduction of C6 Side Chain (ConditionsC)

The respective 6 fluoro benzene was dissolved in THF, KtOBu (1-2 eq.)was added and the mixture allowed to stir at RT for 30 Min. Then asolution of an alcohol R^(6a)OH (1.2 eq.) [Formula (III) where X═O], athiol R^(6a)SH (1.2 eq.) [Formula (III) where X═S], or an amineR^(6a)NH₂ (1.2 eq.) [Formula (III) where X═NH] in DMF was added. Themixture was stirred at 70° C. for 1-24 h. The mixture was partitionedbetween half concentrated brine and ethyl acetate and extracted twicewith ethyl acetate. The combined organic layers were dried over sodiumsulphate, filtered off and concentrated to afford the crude productwhich was optionally further purified by flash column chromatography,trituration or preparative HPLC purification.

General Procedure 2 (GP 2): Introduction of C2 Side Chain

1 eq of the 2-fluorophenyl substrate and 1.5 eq. of the2,4-disubstituted benzene-amine was dissolved in dry THF. Upon coolingto −60° C., 2-3 eq. of potassium tert-butoxide were added and themixture was stirred for 30 min at this temperature. The mixture wasallowed to warm to rt and was stirred until complete consumption of thestarting material. The mixture was then concentrated to afford the crudeproduct which was optionally further purified by flash columnchromatography, trituration or preparative HPLC purification.

General Procedure 3 (GP 3): Hydrolysis of the Benzonitrile

The benzonitrile was dissolved in DMSO and 3 M aq. sodium hydroxidesolution (1.1 eq) was added. The mixture was heated to 63° C. andhydrogen peroxide solution (aq., 30%, 10-80 eq.) was added slowly. Themixture was stirred for another 2 h at 65° C. (bath temp.) and then atrt until TLC or LCMS analysis showed no more turnover. The reactionmixture was poured onto ice water and extracted three times with ethylacetate. The organic layer was washed one time with brine, dried oversodium sulfate, filtered off and concentrated to afford the crudeproduct which was optionally further purified by flash columnchromatography, trituration or preparative HPLC purification.

General Procedure 4a (GP 4a): Clevage of Protecting Groups (BOC Group).

1 eq. of the Boc-protected substrate was suspended in dichloromethaneand treated with excess TFA (5-20 eq.). The mixture was subsequentlystirred at rt until complete consumption of the starting material. Thereaction mixture was concentrated, redissolved in dichloromethane andsodium hydroxide solution (1M, aq.) was added. After phase separationthe organic phase was concentrated to afford the crude product which wasoptionally further purified by flash column chromatography, triturationor preparative HPLC purification.

General Procedure 4b (GP 4b): Clevage of Protecting Groups (Acetonides).

1 eq. of the acetonide-protected substrate was dissolved in THF. Thenhydrochloric acid (aq.; 37%,) was added, and the solution was stirred atrt until complete consumption of the starting material. The mixture wasconcentrated to afford the crude product which was optionally furtherpurified by flash column chromatography, trituration or preparative HPLCpurification.

General Procedure 5 (GP 5): Preparation of Sulfamides

The respective amine was dissolved in DCM and treated subsequently withN-Ethyl-N,N-diisopropyl amin (1.2 eq.). The solution was cooled to 0° C.for 60 min, treated with the respective sulfamoyl chloride (1.1 eq.) andstirred for 30 min at 0° C. and then at RT until TLC or LCMS analysisshowed final turnover. Optionally additional equivalents of base andreagent were added to achieve complete turnover. The formed suspensionwas filtered off, the precipitate was washed with DCM and then dried toafford the pure target compound, which was optionally further purifiedby flash column chromatography, trituration or preparative HPLCpurification.

General Procedure 6 (GP 6): Preparation of Sulfonamides

The respective amine was dissolved in dichloromethane and 1.2 eq. ofpyridine were added. Optionally dichloromethane was replaced by DMF andpyridine was replaced by N-Ethyl-N,N-diisopropyl amin. The mixture wascooled to 3° C. for 10 min before 1.05 eq. of the respective sulfonylchloride were added. The mixture was stirred at rt until TLC or LCMSanalysis showed final turnover. Optionally additional equivalents ofbase and reagent were added to achieve complete turnover. The reactionmixture was diluted with DCM, washed with aqueous half concentratedsodium bicarbonate solution and the aqueous layer extracted twice withDCM. The combined organic layers were dried and concentrated to affordthe crude product, which was optionally further purified by flash columnchromatography, trituration or preparative HPLC purification.

General Procedure 7 (GP 7): Preparation of Ureas

The respective amine (1 eq.) was dissolved in DMF and treatedsubsequently with 1.2 eq. triethylamine and 1.2 eq. of the respectivecarbamoyl chloride. The reaction mixture was stirred at it until TLC orLCMS analysis showed final turnover. Optionally, additional equivalentsof amine and carbamoyl chloride were added to achieve complete turnover.The reaction mixture was subsequently quenched with water, extractedwith DCM, the combined organic layers were dried and concentrated invacuo. Flash column chromatography or trituration or preparative HPLCpurification provided the target compound.

General Procedure 8a (GP 8a): Preparation of Amides

The respective amine (1 eq.) was dissolved in DCM and treated withN-Ethyl-N,N-diisopropyl amin (1.2 eq.). Upon cooling to 0° C., therespective carboxylic acid chloride (1.01 eq.) was added and the mixturewas stirred at rt until TLC or LCMS analysis showed final turnover. Thesuspension was filtered off, the precipitate washed with DCM, dried andconcentrated to afford the crude target compound, which was optionallyfurther purified by flash column chromatography, trituration orpreparative HPLC purification.

General Procedure 8b (GP 8b): Preparation of Amides

The respective amine (1 eq.) was dissolved in DMF. Solutions ofN-Ethyl-N,N-diisopropyl amine (1.3 eq.), HATU (1.3 eq.) and therespective carboxylic acid (1.3 eq.) in DMF where added. The mixture wasstirred for 12 h at rt. The obtained reaction mixtures were purified bypreparative HPLC.

General Procedure 9 (GP 9): Boc Protection of the Diphenyl Amine

The diphenyl amine derivative (1 eq.) was dissolved in THF under Argonand DMAP (0.28 eq.) as well as Di-tert-butyldicarbonate (1.56 eq.) wereadded. The mixture was stirred at rt until TLC or LCMS analysis showedfinal turnover. The mixture was concentrated to afford the crude targetcompound, which was optionally further purified by flash columnchromatography, trituration or preparative HPLC purification.

General Procedure 10 (GP 10): Deprotection of the Diphenyl Amine

The respective BOC protected diphenyl amine (1 eq.) was dissolved inDCM, then TFA (20 eq.) was added. The mixture was stirred at RT rt untilTLC or LCMS analysis showed final turnover and then concentrated. Theresidue was partitioned between ethyl methyl ketone and 1M aq. sodiumhydroxide solution. Then the aqueouse layer was extracted twice withethyl methyl ketone. The combined organic layers were washed with halfconcentrated brine, dried via silicone filter and concentrated to affordthe crude product, which was optionally further purified by flash columnchromatography, trituration or preparative HPLC purification.

General Procedure 11a (GP 11a): Sonogashira Coupling (Conditions A)

The respective iodo-aniline intermediate (1 eq.),bis[(1,2,4,5-eta)-1,5-diphenyl-1,4-pentadien-3-one]-palladium (0.004eq.), copper(I) iodide (0.004 eq.) and triphenyl-phosphine (0.2 eq.)were weighed into a pressure tube and triethyl amine was added. Uponflushing three times with N₂, trimethylsilyl acetylene (6 eq.) wasadded, the pressure tube was sealed and the resulting suspension wasstirred vigorously at 60° C. for 3 h. The mixture was concentrated,redissolved in hexane/ethyl acetate 1:1 and filtered over a NH₂-column(hexane/ethyl acetate 50:50 to 0:100 to pure methanol). The filtrate wasconcentrated to afford the silylated ethynyl compound.

General Procedure 11b (GP 11b): Sonogashira Coupling (Conditions B)

The respective iodo-aniline intermediate (1 eq.) was dissolved in THF,together with the respective alkyne (1.5 eq.), followed bydichlorobis(triphenylphosphine)palladium (II) (Pd(PPh₃)₂Cl₂) (0.5 eq.)and a 1M solution of tetra-N-butylammonium fluoride in THF (5 eq.). Themixture was then allowed to react for 40 min at 110° C. in a microwaveoven (600W; max. 6 bar). The crude reaction mixture was directlysubmitted to preparative HPLC to yield the pure target compound.

General Procedure 12 (GP 12): Desilylation of Trimethylsilyl Alkynes

To a solution of the respective (trimethylsilyl)alkyne in THF (approx.10 mL per g alkyne) is added a 1M solution of tetra-N-butylammoniumfluoride in THF (1 eq.), and the resulting mixture is stirred at roomtemperature until the reaction is completed (typically after approx. 3h). The product is isolated by dilution with water, extracted with e.g.ethyl acetate and purified by column chromatography (if required).

General Procedure 13 (GP 13): Bishydroxylation of the C6 Side Chain

The alkene was dissolved in acetone (60-70 ml per mmol alkene) and H₂O(10-11 ml per mmol alkene), N-methyl-morpholino-N-oxide (1.01-1.9 eq.)was added and the mixture cooled to +3° C. An osmiumtetroxide solution(2.5 weight % in t-BuOH, 0.037-0.1 eq.) was added and the mixture wasstirred for 40 min in an ice bath and then at rt until TLC or LCMSanalysis showed final turnover. Optionally additional equivalents ofN-methyl-morpholino-N-oxide and osmiumtetroxide were added to achievecomplete turnover. The reaction mixture was concentrated, water andethyl acetate were added and the organic layer was extracted three timeswith ethyl acetate. The combined organic layers were washed one timewith brine, dried over sodium sulfate, filtered off, concentrated andoptionally further purified by flash column chromatography, triturationor preparative HPLC purification.

General Procedure 14 (GP 14): Methansulfonate (Mesylate) Formation

The respective alcohol (1 eq.) was dissolved in NMP, treated withmethansulfonyl chloride (1.1 eq.) and collidine (10 eq.) at 0° C. andkept at this temperature until TLC or LCMS analysis showed finalturnover. Preparative HPLC purification of the crude reaction mixtureprovided the target compound. Alternatively, the crude material was usedwithout further purification in the subsequent substitution reaction.

General Procedure 15 (GP 15): Methansulfonate (Mesylate) Substitution

1 eq. of the mesylate (as prepared by GP 14) was dissolved in DMF (2 mLper 100 mg mesylate), treated with 20 eq. of the respective nucleophile,e.g. an amine, and stirred at rt until TLC or LCMS analysis indicatedfinal turnover. Preparative HPLC purification of the crude reactionmixture provided the target compound.

Exemplary HPLC Conditions: (“HPLC conditions A”)

Equipment: Analytical Waters HPLC system Acquity with Waters ZQ 2000single quad MS detector.

Column: Aquity BEH C18 2.1×50 1.7 μm.

Conditions: temperature 60° C.; detection wavelength 214 nm; flow rate0.8 ml/min;

Eluents A: 0.1% formic acid in water, B: 0.1% formic acid in ACN;gradient in each case based on B: 1% to 99% (1.6′) to 99% (0.4′) to 1%(0.1′)

Exemplary HPLC Conditions: (“HPLC conditions B”)

Equipment: Analytical Waters HPLC system Acquity with Waters SQD singlequad MS detector.

Column: Aquity BEH C18 2.1×50 1.7 μm.

Conditions: temperature 60° C.; detection wavelength 254 nm; flow rate0.8 ml/min;

Eluents A: 0.1% formic acid in water, B: ACN; gradient in each casebased on B: 1% to 99% (1.6′) to 99% (0.4′) to 1% (0.1′)

Exemplary HPLC conditions: (“HPLC conditions C”)

Equipment: Analytical Gilson HPLC system (pump P 580, liquid handler215) with Knauer K-2501 UV detector.

Column: Chiralpak IC 5μ150×4.6 mm.

Conditions: temperature 25° C.; detection wavelength 210 nm; flow rate1.0 ml/min;

Eluents: hexane/ethanol 1:1

Solution: 1 mg/ml ethanol

Injection: 5 μL

Intermediate 1.1 Preparation of2-[2-((R)-2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-4,6-difluoro-benzonitrile

In analogy to GP1a, 5 g of 2,4,6-trifluorobenzonitrile (31.83 mmol, 1eq; commercially available) and 4.45 ml of2-((R)-2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (31.83 mmol, 1 eq;commercially available) were dissolved in 150 ml of THF, treated with2.78 g sodium hydride (62.66 mmol; 2 eq.) and stirred at rt for 2 h. Thereaction mixture was poured onto 50 ml of water and extracted threetimes with 100 ml of ethyl acetate each. The organic layer was washedtwice with brine, dried over sodium sulfate, filtered off to afford 5.21g (57.79% yield, 18.39 mmol) of the desired product.

¹H-NMR (d₆-DMSO; 300 MHz): 6.52-6.57 (m, 2H); 4.30-4.36 (m, 1H);4.10-4.23 (m, 3H); 3.67 (dd, 1H); 2.11-2.20 (m, 1H); 2.00-2.08 (m, 1H);1.42 (s, 3H); 1.35 (s, 3H)

MS (ESI): [M+H]⁺=284.

Intermediate 2.1 Preparation ofN′-[3-(2-cyano-3,5-difluorophenoxy)phenyl]-N,N-dimethyl-sulfamide

In analogy to GP1a, 430 mg of 2,4,6-trifluorobenzonitrile (2.74 mmol, 1eq; commercially available) and 596 mg ofN′-(3-hydroxyphenyl)-N,N-dimethyl-sulfamide (2.76 mmol, 1.01 eq;commercially available) were dissolved in 25 ml of THF, treated with 240mg sodium hydride (5.51 mmol, 2.01 eq) and stirred at rt for 48 h. Thereaction mixture was poured onto 100 ml of ice water and extracted threetimes with 70 ml of ethyl acetate each. The organic layer was washed onetime with brine, dried over sodium sulfate, filtered off andconcentrated to afford 1.06 g of crude product. The concentrate waspurified by FlashMaster column chromatography (hexane/ethyl acetate0-20%) to afford 810 mg (84% yield, 2.29 mmol) of the desired product.

¹H-NMR (d₆-DMSO; 300 MHz): 10.19 (s, 1H); 7.45 (dd, 1H); 7.43 (dd, 1H);7.13 (ddd, H); 7.01 (dd, 1H); 6.92 (dd, 1H); 6.74 (ddd, 1H); 2.72 (s,6H).

MS (ESI): [M+H]⁺=354.

Intermediate 2.2 Preparation of[3-(2-Cyano-3,5-difluoro-phenoxy)-phenyl]acetic acid tert-butyl ester

In analogy to GP 1, 3.7 g of 2,4,6-trifluorobenzonitrile (23.6 mmol, 1eq; commercially available) and 5 g of[3-(2-cyano-3,5-difluoro-phenoxy)-phenyl]-carbamic acid tert-butyl ester(23.9 mmol, 1.01 eq; commercially available) were dissolved in 63 ml ofTHF, cooled to 0° C. and treated with 2.08 g sodium hydride (47.56 mmol,2.02 eq.) and stirred at rt for 17 h. The reaction mixture was pouredonto 40 ml of ice water and extracted three times with 100 ml of ethylacetate each. The organic layer was washed one time with brine, driedover sodium sulfate, filtered off and concentrated to afford 9.6 g ofcrude product. The concentrate was purified by flash chromatography(using hexane/ethyl acetate 99/1-50/50) to afford 5.72 g (70% yield,16.5 mmol) of the desired product.

¹H-NMR (d₆-DMSO; 300 MHz): 9.57 (s, 1H); 7.39-7.28 (m, 4H); 6.80 (ddd,1H); 6.62 (ddd, 1H); 1.43 (s, 9H). MS (ESI): [M+H]⁺=347

The following intermediates 2.3 to 2.17 were prepared in analogy to theafore mentioned intermediate compounds by applying general procedure 1a.

Intermediate Structure Name Analytical data 2.3 

2-[(4S,5S)-5-(tert- Butyl-dimethyl- silanyloxymethyl)- 2,2-dimethyl-[1,3]dioxolan-4- ylmethoxy]-4,6- difluoro-benzonitrile MS (ESI): [M +H]⁺ = 414 2.4 

2-(Cyclopent-3- enyloxy)-4,6-difluoro- benzonitrile MS (ESI): [M + H]⁺ =222 2.5 

2,4-Difluoro-6-(4- methyl-pent-3- enyloxy)-benzonitrile MS (ESI): [M +H]⁺ = 238 2.6 

2,4-Difluoro-6-(3- methyl-but-3- enyloxy)-benzonitrile MS (ESI): [M +H]⁺ = 224 2.7 

2,4-Difluoro-6-[3-(2- oxo-pyrrolidin-1-yl)- propoxy]-benzonitrile MS(ESI): [M + H]⁺ = 281 2.8 

2,4-Difluoro-6-(2- imidazol-1-yl- ethoxy)-benzonitrile MS (ESI): [M +H]⁺ = 250 2.9 

2-[3-(1,1-Dioxo-1λ⁶- thiomorpholin-4-yl)- propoxy]-4,6-difluoro-benzonitrile MS (ESI): [M + H]⁺ = 331 2.10

2,4-Difluoro-6-(2- pyridin-3-yl-ethoxy)- benzonitrile MS (ESI): [M + H]⁺= 261 2.11

3-(2-Cyano-3,5-difluoro- phenoxymethyl)- pyrrolidine-1- carboxylic acidtert- butyl ester MS (ESI): [M + H]⁺ = 338 2.12

2-[2-(2-Cyano-3,5- difluoro-phenoxy)- ethyl]-piperidine-1- carboxylicacid tert- butyl ester MS (ESI):  [M + H]⁺ = 367. 2.13

3-(2-Cyano-3,5-difluoro- phenoxymethyl)- piperidine-1- carboxylic acidtert- butyl ester MS (ESI):  [M + H]⁺ = 353. 2.14

2-(2-Cyano-3,5-difluoro- phenoxymethyl)- morpholine-4- carboxylic acidtert- butyl ester MS (ESI):  [M + H]⁺ = 354. 2.15

3-(2-Cyano-3,5-difluoro- phenoxymethyl)- azetidine-1- carboxylic acidtert- butyl ester MS (ESI):  [M + H]⁺ = 325. 2.16

4-(2-Cyano-3,5-difluoro- phenoxy)- piperidine-1- carboxylic acid tert-butyl ester MS (ESI):  [M + H]⁺ = 339. 2.17

2-[2-((R)-2,2-Dimethyl- [1,3]dioloxan-4-yl)- ethoxy]-4,6-difluorobenzoic acid tert- butyl ester MS (CI):  [M + H]⁺ = 359.

Intermediate 3.1 Preparation of2,4-Difluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrile

In analogy to GP 2, 1 g of 2,4,6-trifluoro-benzonitrile (6.37 mmol; 1eq.; commercially available) and 2.26 g 2-fluoro-4-iodo-benzenamine(9.55 mmol, 1.5 eq; commercially available) were dissolved in 100 ml ofTHF. The mixture was cooled to −65° C.; 2.14 g of potassiumtert-butoxide (19.1 mmol, 3 eq; commercially available) were added. Themixture was stirred for 35 min at this temperature and another 21 h atRT. The mixture was stirred into 120 ml of ice water and extracted threetimes with ethyl acetate (100 ml each). The combined organic layers werewashed with brine, dried over sodium sulfate and concentrated to afford4.137 g of crude product. Purification was achieved by flashchromatography (hexane/ethyl acetate) to afford 646 mg (27.13% yield;1.73 mmol) of the target compound.

Intermediate 4.1 Preparation of2(2-Cyano-3,5-difluoro-phenyl)-(2-fluoro-4-iodo-phenyl)-carbamic acidtert-butyl ester

In analogy to GP 9, 205 mg of2,4-Difluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrile (0.55 mmol; 1eq.) were dissolved in THF under argon and 19 mg DMAP (0.16 mmol; 0.28eq.) as well as 186 mg of Di-tert-butyldicarbonate (0.85 mmol; 1.56 eq.)were added. The mixture was stirred at RT for 20 h. The mixture wasconcentrated and purified by flash chromatography (5 g Si-column, usinghexane/ethyl acetate 100/0-70/30) to afford 253 mg (97% yield, 0.53mmol) of the desired product.

¹H-NMR (d₆-DMSO; 300 MHz): 7.77 (br. d, 1H); 7.56-7.66 (m, 2H); 7.25(br. d, 1H); 7.17 (t, 1H); 1.36 (s, 9H).

Intermediate 4.2 Preparation of[3-(3-tert-Butoxycarbonylamino-phenoxy)-2-cyano-5-fluoro-phenyl]-(2-fluoro-4-iodo-phenyl)-carbamicacid tert-butyl ester

500 mg 2(2-Cyano-3,5-difluoro-phenyl)-(2-fluoro-4-iodo-phenyl)-carbamicacid tert-butyl ester (1.05 mmol, 1 eq.) and 412 mg Cs₂CO₃ (1.27 mmol,1.2 eq) were dissolved in 5.5 mL DMF and treated with 265 mg(3-hydroxy-phenyl)-carbamic acid tert-butyl ester (1.27 mmol. 1.2 eq.)dissolved in 5.5 mL DMF. The resulting mixture is stirred at 50° C. for16 h. Extractive workup provided a crude product containing the desiredtarget compound as a mixture of regioisomers along with a smallerfraction of the product of double substitution. This mixture wasadvanced without further purification.

MS (LC-MS): [M+H]⁺=663.

Intermediate 4.3 and 4.4 Preparation of2-(3-Amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrileand2-(3-Amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide

200 mg of the crude reaction mixture from the preparation ofIntermediate 4.2 were dissolved in 2 mL dioxane and treated with 2.5 mL4 N HCl (in dioxane). The resulting mixture was stirred at rt overnight.LCMS analysis showed complete removal of both Boc groups as well aspartial hydrolysis of the nitrite group to the amide. Extractivework-up, concentration and chromatography of the residue gave rise toIntermediate 4.3 (28% yield) as a mixture of regioisomers and toIntermediate 4.4 (37% yield) as a mixture of regioisomers. Theregioisomeric mixtures were further separated by HPLC.

29 mg of the isolated Intermediate 4.3 (0.063 mmol, 1 eq.) weredissolved in 0.75 mL DMSO and treated with 22 μL 3N NaOH solution and0.52 mL H₂O₂ solution and stirred at 65° C. for 2 h. The reactionmixture was diluted with dichloromethane and washed with water. Theorganic layer was dried and concentrated in vacuo to give 19 mg ofIntermediate 4.4 (1.5:1.0 regioisomeric mixture). The regioisomers wereeither separated on this step by HPLC or after subsequenttransformations.

MS (LC-MS) [M+H]⁺=482.

Intermediate 4.5 Preparation of2-(3-Amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benz-amide

In analogy to GP 4a, 163 mg of{3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamicacid tert-butyl ester (0.28 mmol) were suspended in dichloromethane,0.29 ml of TFA (3.78 mmol, 13 eq.) were added and the mixture wasstirred at rt for 4 h. The reaction mixture was concentrated,redissolved in dichloromethane and sodium hydroxide solution (1M, aq.)was added. After phase separation the organic phase was concentrated toafford 129 mg (96%, 0.27 mmol) of the desired product, which required nofurther purification.

¹H-NMR (d₆-DMSO; 300 MHz): 9.23 (s, 1H); 7.84 (sbr, 1H); 7.77 (sbr, 1H);7.66 (dd, 1H); 7.47 (dbr, 1H); 7.21 (dd, 1H); 7.04 (dd, 1H); 6.53 (dbr,1H); 6.42 (dbr, 1H); 6.31-6.26 (m, 2H); 6.07 (dd, 1H).

MS (ESI): [M+H]⁺=482

The following intermediate 4.6 to 4.8 were prepared in analogy to thegeneral procedures described above by using (3-hydroxy-benzyl)-carbamicacid tert-butyl ester or 5-amino-pyridin-3-ol as nucleophilic startingmaterial in the first case followed by acidic Boc cleavage.

Intermediate Structure Name Analytical Data 4.6

{3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-benzyl}- carbamic acid tert- butyl ester MS (ESI): [M + H]⁺ =596. 4.7

[3-(5-Amino-pyridin- 3-yloxy)-2-cyano-5- fluoro-phenyl]-(2-fluoro-4-iodo- phenyl)-carbamic acid tert-butyl ester ¹H-NMR: (d6-DMSO,300 MHz) 7.82 (d, 1H); 7.78 (dd, 1H); 7.62-7.55 (m, 2H); 7.17 (dd, 1H);7.08 (dd, 1H); 6.90 (dbr, 1H); 6.65 (dd, 1H); 5.64 (sbr, 2H); 1.38 (s,9H). MS (LC-MS): [M + H]⁺ = 565  4.8

2-(5-Amino-pyridin-3- yloxy)-4-fluoro-6-(2- fluoro-4-iodo- phenylamino)-benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 9.03 (s, 1H); 7.84 (sbr, 2H); 7.71(d, 1H); 7.66 (dd, 1H); 7.55 (d, 1H); 7.47 (dbr, 1H); 7.20 (dd, 1H);6.56 (dbr, 1H); 6.53 (dd, 1H); 6.19 (dd, 1H); 5.52 (s, 2H). MS (LC-MS):[M + H]⁺ = 483.

The following intermediates 5.1 to 5.14 were prepared in analogy toprocesses described above and below by nucleophilic displacement of afluorine by the respective anilines (GP 2) and optionally subsequentnitrile hydrolysis (GP 3).

Intermediate Structure Name Analytical Data 5.1 

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-((2S,3S)-2,3,4-trihydroxy-butoxy)- benzonitrile MS (ESI): [M + H]+ = 477. 5.2 

2-[2-((R)-2,2-Dimethyl- [1,3]dioxolan-4-yl)- ethoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzonitrile 1H-NMR: (CDCl3, 300 MHz)7.46-7.54 (m, 2H); 7.08 (t, 1H); 6.25-6.30 (m, 2H); 6.18 (dd, 1H);4.29-4.28 (m, 1H); 4.00-4.20 (m, 3 H); 3.68 (dd, 1H); 1.94-2.20 (m, 2H);1.43 (s, 3H); 1.38 (S, 3H). MS (ESI): [M + H]+ = 501. 5.3 

2-[2-((R)-2,2-Dimethyl- [1,3]dioxolan-4-yl)- ethoxy]-4-fluoro-6-(2-fluoro- phenylamino)- benzonitrile MS (ESI): [M + H]+ = 375. 5.4 

2-(4-Chloro-2-fluoro- phenylamino)-6-[2- ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)- ethoxy]-4-fluoro- benzonitrile MS (ESI): [M + H]+ =409. 5.5 

2-(4-Bromo-2-fluoro- phenylamino)-6-[2- ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)- ethoxy]-4-fluoro- benzonitrile MS (ESI): [M + H]+ =454. 5.6 

2-[2-((R)-2,2-Dimethyl- [1,3]dioxolan-4-yl)- ethoxy]-4-fluoro-6-(4-iodo- phenylamino)- benzonitrile MS (ESI): [M + H]+ = 483. 5.7 

2-[2-((R)-2,2-Dimethyl- [1,3]dioxolan-4-yl)- ethoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzoic acid tert- butyl ester MS (ESI):[M + H]+ = 576. 5.8 

2-[2-((R)-2,2-Dimethyl- [1,3]dioxolan-4-yl)- ethoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzonitrile 1H-NMR: (CDCl3, 300 MHz)10.86 (s, 1H); 8.06 (br. s, 1H); 7.46 (dd, 1H); 7.41 (dd, 1H); 7.10 (t,1H); 6.36 (ddd, 1H); 6.10 (dd, 1H); 5.79 (br. s, 1H); 4.09 - 4.30 (m,4H); 3.60 (t, 1H); 2.02-2.12 (m, 2H); 1.41 (s, 3H); 1.34 (s, 3H). MS(ESI): [M + H]+ = 519. 5.9 

2-[2-((R)-2,2-Dimethyl- [1,3]dioxolan-4-yl)- ethoxy]-4-fluoro-6-(2-fluoro- phenylamino)- benzamide MS (ESI): [M + H]+ = 393. 5.10

2-(4-Chloro-2-fluoro- phenylamino)-6-[2- ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)- ethoxy]-4-fluoro- benzamide MS (ESI): [M + H]+ =427. 5.11

2-(4-Bromo-2-fluoro- phenylamine)-6-[2- ((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)- ethoxy]-4-fluoro- benzamide 1H-NMR: (CDCl3, 300MHz) 10.89 (br. s, 1H); 8.15 (br. s, 1H); 7.24-7.37 (m, 4H); 6.37 (br.d, 1H); 6.15 (dd, 1H); 5.76 (br. s, 1H); 4.15-4.35 (m, 4H); 3.65 (t,1H); 2.08-2.23 (m, 2H); 1.46 (s, 3H); 1.41 (s, 3H). MS (ESI): [M + H]+ =472. 5.12

2-[2-((R)-2,2-Dimethyl- [1,3]dioxolan-4-yl)- ethoxy]-4-fluoro-6-(4-iodo- phenylamino)- benzamide 1H-NMR: (CDCl3, 300 MHz) 10.80 (br. s,1H); 8.08 (br. s, 1H); 7.61 (d, 2H); 6.97 (d, 2H); 6.51 (dd, 1H); 6.07(dd, 1H); 5.66 (br. s, 1H); 4.08-4.29 (m, 4H); 3.61 (t, 1H); 2.05-2.13(m, 2H); 1.41 (s, 3H); 1.35 (s, 3H). MS (ESI): [M + H]+ = 501. 5.13

2-[2-((R)-2,2-Dimethyl- [1,3]dioxolan-4-yl)- ethoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzoic acid MS (ESI): [M + H]+ = 520.5.14

{2-Carbamoyl-3-[3- (3,3-dimethyl- ureido)-phenoxy]-5- fluoro-phenyl}-(2-fluoro-4-iodo- phenyl)-carbamic acid tert-butyl ester MS (ESI): [M + H]+= 651.

Intermediate 6.1 Preparation of{2-Cyano-3-[3-(3,3-dimethyl-ureido)-phenoxy]-5-fluoro-phenyl}-(2-fluoro-4-iodo-phenyl)-carbamicacid tert-butyl ester

In analogy to GP 1a, 100 mg of{2-Cyano-3-[3-(3,5-difluorophenyl)-(2-fluoro-4-iodo-phenyl)-carbamicacid tert-butyl ester (0.21 mmol, 1 eq.) and 39.14 mg ofN′-(3-hydroxyphenyl)-N,N-diphenylsulfamide (0.22 mmol, 1.03 eq;commercially available) were dissolved in 5 ml THF and treated with24.84 mg sodium hydride (0.57 mmol; 2.7 eq.) and stirred at rt for 27 h.The reaction mixture was poured onto 20 ml of ice water and extractedthree times with 30 ml of ethyl acetate each. The organic layer waswashed one time with brine, dried over sodium sulfate, filtered off andconcentrated to afford 160 mg of crude product. The concentrate waspurified by flash chromotography to afford 53 mg (40.2% yield, 0.085mmol) of the desired product.

¹H-NMR (d₆-DMSO; 300 MHz): 8.49 (s, 1H); 7.83 (dd, 1H); 7.64 (dbr, 1H);7.43 (s, 1H); 7.42 (dd, 1H); 7.34 (dd, 1H); 7.22 (dd, 1H); 7.09 (dd,1H); 6.77 (dbr, 2H); 2.93 (s, 6H); 1.43 (s, 9H).

MS (ESI) [M+H]⁺=635.

Example 1.0 Preparation ofN′-[3-[2-cyano-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy]phenyl]-N,N-dimethyl-sulfamide

In analogy to GP 2, 410 mg ofN′-[3-(2-cyano-3,5-difluorophenoxy)phenyl]-N,N-dimethyl-sulfamide (1.16mmol, 1 eq) and 413 mg of 2-fluoro-4-iodo-benzenamine (1.74 mmol, 1.5eq; commercially available) were dissolved in 20 ml of THF. Upon coolingto −60° C., 393 mg of potassium tert-butoxide were added and the mixturestirred for 30 min at this temperature. The mixture was allowed to warmto it slowly and was stirred for another 22 h at rt. The mixture wasthen concentrated and purified (FlashMaster column chromatography,hexane/ethyl acetate 0-30%) to afford 354 mg of the desired product.

¹H-NMR (d₆-DMSO; 300 MHz): 10.15 (s, 1H); 8.84 (s, 1H); 7.75 (dd, 1H);7.58 (ddd, 1H); 7.40 (dd, 1H); 7.15 (dd, 1H); 7.08 (ddd, 1H); 6.96 (dd,1H); 6.87 (ddd, 1H); 6.28 (ddd, 1H); 6.18 (dd, 1H); 2.72 (s, 6H).

MS (ESI): [M+H]⁺=571 Example 1.1 Preparation of{3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamicacid tert-butyl ester

In analogy to GP 2, 500 mg of[3-(2-Cyano-3,5-difluoro-phenoxy)-phenyl]-acetic acid tert-butyl ester(1.44 mmol, 1 eq) and 513 mg of 2-fluoro-4-iodo-benzenamine (2.17 mmol,1.5 eq; commercially available) were dissolved in 13 ml of THF. Uponcooling to 3° C., 486 mg (4.33 mmol, 3 eq.) of potassium tert-butoxidewere added and the mixture stirred for 30 min at this temperature. Themixture was allowed to come to rt slowly and was stirred for another 20h at rt. After addition of 162 mg (1.44 mmol, 1 eq.) of potassiumtert-butoxide the mixture was stirred at rt for another 2 h. Thereaction mixture was poured onto 30 ml of ice water and 30 ml ethylacetate were added. The aqueous phase was extracted three times with 40ml of ethyl acetate each. The combined organic layers were washed onetime with brine, dried over sodium sulfate, filtered off andconcentrated to afford 750 mg of crude product. The concentrate waspurified by flash chromatography (hexane/ethyl acetate 99/1-60/40) toafford 406 g (50% yield, 0.72 mmol) of the desired product.

¹H-NMR (d₆-DMSO; 300 MHz): 9.54 (s, 1H); 8.77 (s, 1H); 7.69 (dd, 1H);7.53 (dbr, 1H); 7.34-7.24 (m, 3H); 7.11 (dd, 1H); 6.75 (ddd, 1H); 6.21(ddd, 1H); 6.07 (dd, 1H); 1.43 (s, 9H).

MS (ESI): [M+H]⁺=564

The following example compounds 1.2 to 1.11 were prepared in analogy toand general procedure 2:

Example Structure Name Analytical data 1.2

2-(Cyclopent-3- enyloxy)-4-fluoro-6- (2-fluoro-4-iodo- phenylamino)-benzonitrile MS (ESI): [M + H]⁺ = 439. 1.3

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(4-methyl-piperazin-1-yl)- propoxy]-benzonitrile MS (ESI): [M + H]⁺ = 513. 1.4

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(4-methyl-pent-3-enyloxy)-benzonitrile MS (ESI): [M + H]⁺ = 455. 1.5

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3-methyl-but-3-enyloxy)-benzonitrile MS (ESI): [M + H]⁺ = 441. 1.6

3-[2-Cyano-5-fluoro- 3-(2-fluoro-4-iodo- phenylamino)- phenoxymethyl]-pyrrolidine-1- carboxylic acid tert- butyl ester MS (ESI): [M + H]⁺ =556. 1.7

2-{2-[2-Cyano-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-ethyl}- piperidine-1- carboxylic acid tert- butyl ester MS(ESI): [M + H]⁺ = 584. 1.8

3-[2-Cyano-5-fluoro- 3-(2-fluoro-4-iodo- phenylamino)- phenoxymethyl]-piperidine-1- carboxylic acid tert- butyl ester MS (ESI): [M + H]⁺ =570. 1.9

2-[2-Cyano-5-fluoro- 3-(2-fluoro-4-iodo- phenylamino)- phenoxymethyl]-morpholine-4- carboxylic acid tert- butyl ester MS (ESI): [M + H]⁺ =572.  1.10

3-[2-Cyano-5-fluoro- 3-(2-fluoro-4-iodo- phenylamino)- phenoxymethyl]-azetidine-1- carboxylic acid tert- butyl ester MS (ESI): [M + H]⁺ = 542. 1.11

4-[2-Cyano-5-fluoro- 3-(2-fluoro-4-iodo- phenylamino)-phenoxy]-piperidine- 1-carboxylic acid tert-butyl ester MS (ESI): [M +H]⁺ = 556.

Example 2.0 Preparation of{3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamicacid tert-butyl ester

In analogy to GP 3, 386 mg of{3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamicacid tert-butyl ester (0.69 mmol, 1 eq) were dissolved in 4.8 ml of DMSOand 0.24 ml of 3 M aq. sodium hydroxide solution (0.72 mmol, 10-80 eq)were added. The mixture was heated to 63° C. and 1.85 ml of hydrogenperoxide solution (aq., 30%) were added over the course of 20 min. Themixture was stirred for another 2 h at 65° C. (bath temp.). The reactionmixture was poured onto 175 ml of ice water. 300 ml of ethyl acetatewere added and the phases separated. The aqueous phase was extracted onemore time with 150 ml of ethyl acetate. The combined organic layers werewashed one time with brine, dried over sodium sulfate, filtered off andconcentrated. The concentrate was purified (FlashMaster columnchromatography, hexane/ethyl acetate 99/1-60/40) to afford 169 mg (42%yield, 0.29 mmol) of the desired product.

¹H-NMR (d₆-DMSO; 300 MHz): 9.46 (s, 1H); 9.12 (s, 1H); 7.83 (sbr, 2H);7.66 (dd, 1H); 7.47 (dbr, 1H); 7.30-7.17 (m, 4H); 6.65 (ddd, 1H); 6.54(dbr, 1H); 6.06 (dd, 1H); 1.42 (s, 9H).

MS (ESI): [M+H]⁺=582

Example Compound 2.1 Preparation of2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide

In analogy to GP 3, 210 mg ofN′-[3-[2-cyano-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy]phenyl]-N,N-dimethyl-sulfamide (0.37 mmol, 1 eq) weredissolved in 3 ml of DMSO and 0.14 ml of 3 M aq. sodium hydroxidesolution (0.41 mmol, 1.1 eq) were added. The mixture was heated to 63°C. and 0.8 ml of hydrogen peroxide solution (aq., 30%) were added duringthe course of 1.5 h. The mixture was stirred for another 2 h at 65° C.(bath temp.) and for 18 h at rt. The reaction mixture was poured onto 80ml of ice water and extracted three times with 50 ml of ethyl acetateeach. The organic layer was washed one time with brine, dried oversodium sulfate, filtered off and concentrated to afford 402 mg of crudeproduct. The concentrate was purified (FlashMaster column, hexane/ethylacetate 0-50%) to afford 94 mg (43% yield, 0.16 mmol) of the desiredproduct.

¹H-NMR (d₆-DMSO; 300 MHz): 10.05 (s, 1H); 9.08 (s, 1H); 7.90 (sbr, 1H);7.87 (sbr, 1H); 7.70 (dd, 1H); 7.52 (ddd, 1H); 7.33 (dd, 1H); 7.25 (dd,1H); 7.00 (ddd, 1H); 6.94 (dd, 1H); 6.75 (ddd, 1H); 6.61 (ddd, 1H); 6.16(dd, 1H); 2.71 (s, 6H).

MS (ESI): [M+H]⁺=589

The following example compounds 2.2 to 2.15 were prepared in analogy toexample compounds 2.0 and 2.1 by applying GP 3 to the respectivenitriles.

Example Structure Name Analytical data 2.2 

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(2-oxo-pyrrolidin-1-yl)- propoxy]-benzamide 1H-NMR: (d6-DMSO, 300 MHz) 9.47 (s,1H); 7.94 (sbr, 1H); 7.81 (sbr, 1H); 7.45 (ddd, 1H); 7.19 (dd, 1H); 6.42(d, 2H); 3.92 (dd, 2H); 3.37-3.25 (m, 4H); 2.18 (dd, 2H); 1.96-1.83 (m,4H). MS (ESI): [M + H+ = 516 2.3 

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(4-methyl-pent-3-enyloxy)-benzamide MS (ESI): [M + H]⁺ = 473. 2.4 

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3-methyl-but-3-enyloxy)-benzamide MS (ESI): [M + H]⁺ = 459. 2.5 

2-(Cyclopent-3- enyloxy)-4-fluoro-6- (2-fluoro-4-iodo- phenylamino)-benzamide MS (ESI): [M + H]+ = 457. 2.6 

3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxymethyl]- pyrrolidine-1- carboxylic acid tert- butyl ester MS(ESI): [M + H]+ = 574. 2.7 

2-[2-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-ethyl}- piperidine-1- carboxylic acid tert- butyl ester MS(ESI): [M + H]+ = 602. 2.8 

3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxymethyl]- piperidine-1- carboxylic acid tert- butyl ester MS(ESI): [M + H]+ = 588. 2.9 

2-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxymethyl]- morpholine-4- carboxylic acid tert- butyl ester MS(ESI): [M + H]+ = 590. 2.10

3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxymethyl]- azetidine-1- carboxylic acid tert- butyl ester MS (ESI):[M + H]+ = 560. 2.11

{3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-propyl}- carbamic acid tert- butyl ester MS (ESI): [M + H]+ =548. 2.12

4-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-piperidine- 1-carboxylic acid tert-butyl ester MS (ESI): [M +H]+ = 574. 2.13

4-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-phthalic acid MS (ESI): [M + H]⁺ = 555. 2.14

4-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-phthalic acid 2-methyl ester MS (ESI): [M + H]⁺ = 569. 2.15

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(6-trifluoromethyl-pyridin-2-yloxy)- benzamide MS (ESI): [M + H]⁺ = 536.

The following example compounds 2.16 to 2.17 were prepared in analogy toexample compounds 2.1 by using the respective anilines as startingmaterial.

Example Structure Name Analytical data 2.16

2-{3- [(dimethylsulfamoyl) amino]phenoxy}-4- fluoro-6-[(4-iodophenyl)amino] benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 9.96 (br. s, 1H);8.75 (s, 1H); 7.82 (br. s, 1H); 7.75 (br. s, 1H); 7.57 (d, 2H); 7.27 (t,1H); 6.98 (d, 2H); 6.94 (dd, 1H); 6.89 (t, 1H); 6.68-6.72 (m, 2H); 6.10(dd, 1H); 2.66 (s, 6H). MS (ESI): [M + H]⁺ = 571. 2.17

2-{3- [(dimethylsulfamoyl) amino]phenoxy}-4- fluoro-6-[(4-iodo-2-methylphenyl)amino] benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 10.02 (s, 1H);9.95 (s, 1H); 7.84 (br. s, 1H); 7.81 (br. s, 1H); 7.61 (d, 1H); 7.48(dd, 1H); 7.28 (t, 1H); 7.05 (d, 1H); 6.95 (dd, 1H); 6.90 (t, 1H); 6.73(dd, 1H); 6.38 (dd, 1H); 6.01 (dd, 1H); 2.65 (s, 6H); 2.12 (s, 3H). MS(ESI): [M + H]⁺ = 585.

The following example compounds 2.18 to 2.20 were prepared in analogy toexample compounds 2.1 by using the respective higher fluorinatedstarting materials:

Example Structure Name Analytical data 2.18

6-{3- [(dimethylsulfamoyl) amino]phenoxy}-3,4- difluoro-2-[(2-fluoro-4-iodophenyl)amino]- benzamide MS (LC-MS): [M + H]⁺ = 607 2.19

{3-[2-Carbamoyl- 4,5,6-trifluoro-3-(2- fluoro-4-iodo- phenylamino)-phenoxy]-phenyl}- carbamic acid tert-butyl ester MS (LC-MS): [M + H]⁺ =618. 2.20

2-{3- [(dimethylsulfamoyl) amino]phenoxy}- 3,4,5-trifluoro-6-[(2-fluoro-4- iodophenyl)amino]- benzamide MS (LC-MS): [M + H]⁺ = 625.

The following example compounds 3.1 to 3.3 were prepared by applying GP4a (or other standard deprotection conditions as known to the personskilled in the art) to the respective protected substrate, which havebeen prepared as described above.

Example Structure Name Analytical data 3.1

2-[3-(3,3-Dimethyl- ureido)-phenoxy]-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR (d₆-DMSO; 400 MHz): 9.17 (s, 1H);8.37 (s, 1H); 7.84 (sbr, 1H); 7.81 (sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr,1H); 7.31-7.18 (m, 4H); 6.65 (dbr, 1H); 6.54 (dbr, 1H); 6.07 (dd, 1H);2.87 (s, 6H). MS (ESI): [M − H]− = 553. 3.2

3-{3-[2-Cyano-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-phenyl}- 1,1-dimethyl-urea MS (ESI): [M +H]⁺ = 535. 3.3

2-(3-Aminomethyl- phenoxy)-4-fluoro-6- (2-fluoro-4-iodo- phenylamino)-benzamide; compound with formic acid MS (ESI): [M + H]⁺ = 496.

Example 4.1 Preparation of2-(3,3-Dioxo-2,3-dihydro-3λ⁶-benzo[1,3]oxathiol-5-yloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide

2-(3,3-Dioxo-2,3-dihydro-3λ⁶-benzo[1,3]oxathiol-5-yloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamidewas prepared by applying the general procedures described above in 28%yield.

¹H-NMR (d₆-DMSO; 400 MHz): 8.94 (s, 1H); 7.89 (sbr, 1H); 7.87 (sbr, 1H);7.70 (d, 1H); 7.66 (dd, 1H); 7.52-7.45 (m, 2H); 7.37 (d, 1H); 7.20 (dd,1H); 6.53 (dd, 1H); 6.06 (dd, 1H); 5.38 (s, 2H).

MS (ESI): [M+H]⁺=559.

The following example compounds 4.2 to 4.38 were prepared by applyingthe described procedures above and below:

Example Structure Name Analytical data 4.2

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3-nitro-phenoxy)-benzamide MS (ESI): [M + H]⁺ = 512 4.3

2-(Benzo[1,3]dioxol- 5-yloxy)-4-fluoro-6- (2-fluoro-4-iodo-phenylamino)- benzamide MS (ESI): [M + H]⁺ = 511 4.4

Dimethyl-carbamic acid 3-[2-carbamoyl- 5-fluoro-3-(2-fluoro-4-iodo-phenylamino)- phenoxy]-phenyl ester ¹H-NMR (d₆-DMSO; 300 MHz):9.05 (s, 1H); 7.89 (sbr, 2H); 7.70 (dd, 1H); 7.52 (dd, 1H); 7.43 (dd,1H); 7.25 (dd, 1H); 7.02-6.94 (m, 3H); 6.60 (dd, 1H); 6.15 (dd, 1H);3.04 (s, 3H); 2.91 (s, 3H). MS (ESI): [M + H]⁺ = 554 4.5

2-(4-Acetylamino- phenoxy)-4-fluoro-6- (2-fluoro-4-iodo- phenylamino)-benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 9.97 (s, 1H); 9.13 (s, 1H); 7.85(sbr, 1H); 7.83 (sbr, 1H); 7.65 (dd, 1H); 7.59 (d, 2H); 7.47 (dbr, 1H);7.20 (dd, 1H); 7.07 (d, 2H); 6.49 (dbr, 1H); 5.93 (dd, 1H); 2.00 (s,3H). MS (ESI): [M + H]⁺ = 524 4.6

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(1-methyl-piperidin-4-yloxy)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.65 (s, 1H);7.80 (br. s, 1H); 7.63 (dd, 1H); 7.57 (br. s, 1H); 7.45 (d, 1H); 7.17(t, 1H); 6.54 (dd, 1H); 6.38 (dd, 1H); 4.42-4.52 (m, 1H); 2H obscured bysolvent signal; 2.11-2.23 (m, 5H); 1.84-1.93 (m, 2H); 1.62-1.73 (m, 2H).MS (ESI): [M + H]⁺ = 488. 4.7

4-{2-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-ethyl}- piperazine-1- carboxylic acid tert- butyl ester ¹H-NMR:(d6-DMSO, 400 MHz) 10.68 (s, 1H); 8.44 (br. s, 1H); 7.77 (br. s, 1H);7.65 (dd, 1H); 7.47 (d, 1H); 7.22 (t, 1H); 6.50 (dd, 1H); 6.39 (dd, 1H);4.19 (t, 1H); 3.25-3.28 (m, 4H); 2.66 (t, 2H); 2.34- 2.38 (m, 4H); 1.36(s, 9H). MS (ESI): [M + H]⁺ = 603. 4.8

6-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-indole-1- carboxylic acid tert- butyl ester MS (ESI): [M + H]⁺= 606 4.9

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[4- (methanesulfonyl-methyl-amino)- phenoxy]-benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 9.04 (s,1H); 7.86 (sbr, 2H); 7.66 (dd, 1H); 7.47 (dbr, 1H); 7.42 (m, 2H); 7.21(dd, 1H); 7.11 (m, 2H); 6.56 (dbr, 1H); 6.14 (dd, 1H); 3.19 (s, 3H);2.91 (s, 3H). MS (ESI): [M + H]⁺ = 574 4.9

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3- hydrazinocarbonyl-phenoxy)-benzamide MS (ESI): [M + H]⁺ = 525 4.10

Acetic acid (1S,4R)-4- [2-carbamoyl-5- fluoro-3-(2-fluoro-4-iodo-phenylamino)- phenoxy]-cyclopent- 2-enyl ester MS (ESI): [M + H]⁺ =473. 4.11

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-((1R,4S)-4-hydroxy-cyclopent-2-enyloxy)- benzamide MS (ESI): [M + H]⁺ = 515. 4.12

Dimethyl-sulfamic acid 3-[2-carbamoyl- 5-fluoro-3-(2-fluoro-4-iodo-phenylamino)- phenoxy]-phenyl ester MS (ESI): [M + H]⁺ = 590.4.13

2-[2-((S)-2,2- Dimethyl- [1,3]dioxolan-4-yl)- ethoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide MS (ESI): [M + H]⁺ = 519 4.14

(R)-2-[2-Carbamoyl- 5-fluoro-3-(2-fluoro- 4-iodo-phenylamino)-phenoxymethyl]- pyrrolidine-1- carboxylic acid tert- butyl ester MS(ESI): [M + H]⁺ = 574. 4.15

(S)-2-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxymethyl]- pyrrolidine-1- carboxylic acid tert- butyl ester MS(ESI): [M + H]⁺ = 574. 4.16

2-[3- [[(dimethylamino) sulfonyl]amino] phenoxy]- N-ethyl-4-fluoro-6-[(2-fluoro-4- iodophenyl)amino]- benzamide ¹H-NMR: (d6-DMSO, 300 MHz)9.97 (s, 1H); 8.60 (s, 1H); 8.41 (t, 1H); 7.67 (dd, 1H); 7.46 (ddd, 1H);7.25 (t, 1H); 7.18 (t, 1H); 6.92 (ddd, 1H); 6.86 (t, 1H); 6.65 (ddd,1H); 6.58 (ddd, 1H); 6.23 (dd, 1H); 3.14 (m, 2H); 2.65 (s, 6H). MS(ESI): [M + H]⁺ = 617. 4.17

2-[3- [[(dimethylamino) sulfonyl]amino] phenoxy]--4-fluoro-6-[(2-fluoro-4- iodophenyl)amino]- N-methyl-benzamide ¹H-NMR: (d6-DMSO,300 MHz) 10.0 (s, 1H); 8.69 (s, 1H); 8.40 (br q, 1H); 7.65 (dd, 1H);7.47 (br d, 1H); 7.27 (t, 1H); 7.17 (t, 1H); 6.94 (br d, 1H); 6.88 (s,1H); 6.68 (dd, 1H); 6.53 (dd, 1H); 6.14 (dd, 1H); 2.66 (s, 9H). MS(ESI): [M + H]⁺ = 603. 4.18

2-[3- [[(dimethylamino) sulfonyl]amino] phenoxy]--4-fluoro-6-[(2-fluoro-4- iodophenyl)amino]- N-(2-hydroxy-ethyl)- benzamide¹H-NMR: (d6-DMSO, 400 MHz) 10.00 (s, 1H); 8.66 (s, 1H); 8.39 (t, 1H);7.65 (dd, 1H); 7.47 (br. d, 1H); 7.26 (t, 1H); 7.18 (t, 1H); 6.94 (dd,1H); 6.86 (t, 1H); 6.68 (dd, 1H); 6.54 (br d, 1H); 6.18 (dd, 1H); 4.66(t, 1H); 3.34 (m, 2H); 3.21 (m, 2H); 2.66 (s, 6H). MS (ESI): [M + H]⁺ =633. 4.19

2-[3- [[(dimethylamino) sulfonyl]amino] phenoxy]--4-fluoro-6-[(2-fluoro-4- iodophenyl)amino]- N-(2-hydroxy-propyl)- benzamide¹H-NMR: (d6-DMSO, 400 MHz) 10.00 (s, 1H); 8.61 (s, 1H); 8.44 (t, 1H);7.65 (dd, 1H); 7.46 (br. d, 1H); 7.26 (t, 1H); 7.18 (t, 1H); 6.94 (dd,1H); 6.87 (t, 1H); 6.69 (dd, 1H); 6.55 (br d, 1H); 6.17 (dd, 1H); 4.37(t, 1H); 3.33 (q, 2H); 3.19 (q, 2H); 2.66 (s, 6H); 1.50 (quint. 2H). MS(ESI): [M + H]⁺ = 647. 4.20

2-[3- [[(dimethylamino) sulfonyl]amino] phenoxy]--4-fluoro-6-[(2-fluoro-4- iodophenyl)amino]- N-((R)-2-hydroxy- 1-methyl-ethyl)-benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.98 (s, 1H); 8.55 (s, 1H); 8.17(d, 1H); 7.65 (dd, 1H); 7.47 (dd, 1H); 7.24 (t, 1H); 7.17 (t, 1H); 6.91(dd, 1H); 6.85 (t, 1H); 6.64 (dd, 1H); 6.56 (br d, 1H); 6.25 (dd, 1H);4.72 (t, 1H); 3.86 (m, 1H); 3.10-3.27 (m, 2H); 2.66 (s, 6H); 0.94 (d,2H). MS (ESI): [M + H]⁺ = 647. 4.21

2-[3- [[(dimethylamino) sulfonyl]amino] phenoxy]--4-fluoro-6-[(2-fluoro-4- iodophenyl)amino]- N-((S)-2-hydroxy- 1-methyl-ethyl)-benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.99 (s, 1H); 8.54 (s, 1H); 8.17(d, 1H); 7.65 (dd, 1H); 7.47 (dd, 1H); 7.25 (t, 1H); 7.17 (t, 1H); 6.91(dd, 1H); 6.85 (t, 1H); 6.65 (dd, 1H); 6.56 (br d, 1H); 6.25 (dd, 1H);4.72 (t, 1H); 3.86 (m, 1H); 3.10-3.27 (m, 2H); 2.66 (s, 6H); 0.94 (d,3H). MS (ESI): [M + H]⁺ = 647. 4.22

2-[3- [[(dimethylamino) sulfonyl]amino] phenoxy]--4-fluoro-6-[(2-fluoro-4- iodophenyl)amino]- N-((R)-2-hydroxy- propyl)-benzamide¹H-NMR: (d6-DMSO, 300 MHz) 10.00 (s, 1H); 8.63 (s, 1H); 8.38 (t, 1H);7.65 (dd, 1H); 7.47 (dd, 1H); 7.27 (t, 1H); 7.17 (t, 1H); 6.94 (dd, 1H);6.89 (t, 1H); 6.70 (dd, 1H); 6.50 (br d, 1H); 6.14 (dd, 1H); 4.67 (d,1H); 3.63 (m, 1H); 3.03-3.18 (m, 2H); 2.66 (s, 6H); 0.93 (d, 3H). MS(ESI): [M + H]⁺ = 647. 4.23

2-[3- [[(dimethylamino) sulfonyl]amino] phenoxy]--4-fluoro-6-[(2-fluoro-4- iodophenyl)amino]- N-((S)-2-hydroxy- propyl)-benzamide¹H-NMR: (d6-DMSO, 300 MHz) 10.01 (s, 1H); 8.62 (s, 1H); 8.38 (t, 1H);7.65 (dd, 1H); 7.47 (dd, 1H); 7.27 (t, 1H); 7.17 (t, 1H); 6.94 (dd, 1H);6.89 (t, 1H); 6.71 (dd, 1H); 6.52 (br d, 1H); 6.14 (dd, 1H); 4.67 (d,1H); 3.62 (m, 1H); 3.03-3.18 (m, 2H); 2.66 (s, 6H); 0.93 (d, 3H). MS(ESI): [M + H]⁺ = 647. 4.24

{4-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)- phenoxy]-cyclohexyl}-carbamic acid tert-butyl ester ¹H-NMR: (d6-DMSO, 400 MHz)9.73 (s, 1H); 7.74 (s, 1H); 7.63 (dd, 1H); 7.55 (s, 1H); 7.44 (d, 1H);7.17 (t, 1H); 6.81 (d, 1H); 6.56 (dd, 1H); 6.37 (dd, 1H); 4.30-4.37 (m,1H); 3.19-3.28 (m, 1H); 2.00-2.08 (m, 2H); 1.73-1.78 (m, 2H); 1.39-1.50(m, 2H); 1.34 (s, 9H); 1.25-1.31 (m, 2H). MS (ESI): [M + H]⁺ = 588. 4.25

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-((S)-1-methyl-pyrrolidin-2- ylmethoxy)- benzamide ¹H-NMR: (d6-DMSO, 400 MHz) 10.34 (s,1H); 8.23 (s, 1H); 7.72 (s, 1H); 7.64 (d, 1H); 7.46 (d, 1H); 7.20 (t,1H); 6.48 (dd, 1H); 6.39 (dd, 1H); 4.12 (dd, 1H); 3.95 (dd, 1H);2.92-2.97 (m, 1H); 2.50- 2.54 (m, 1H); 2.25 (s, 3H); 2.17 (m, 1H);1.84-1.95 (m, 1H); 1.62-1.74 (m, 3H). 4.26

2-((RS)-1-Ethyl- pyrrolidin-2- ylmethoxy)-4-fluoro- 6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 400 MHz) 10.44 (s, 1H); 8.35(s, 1H); 7.73 (s, 1H); 7.64 (d, 1H); 7.46 (d, 1H); 7.21 (t, 1H); 6.47(dd, 1H); 6.40 (dd, 1H); 4.12 (dd, 1H); 3.97 (dd, 1H); 3.04-3.09 (m,1H); 2.79 (dq, 2H); 2.66-2.72 (m, 1H); (s, 3H); 2.17 (dq, 2H); 1.82-1.92 (m, 1H); 1.62-1.75 (m, 3H); 0.96 (t, 3H). 4.27

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(1-methyl-1H-pyrazol-4-yloxy)- benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 9.06 (s, 1H);7.86 (sbr, 1H); 7.83 (sbr, 1H); 7.75 (s, 1H); 7.65 (dd, 1H); 7.47 (dbr,1H); 7.40 (d, 1H); 7.18 (dd, 1H); 6.46 (dbr, 1H); 6.11 (dd, 1H); 3.79(s, 3H). MS (ESI): [M − H]⁻ = 469. 4.28

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3- pentafluoroethyl-phenoxy)-benzamide ¹H-NMR (d₆-DMSO; 400 MHz): 8.91 (s, 1H); 7.93 (sbr,1H); 7.85 (sbr, 1H); 7.69-6.62 (m, 2H); 7.51-7.45 (m, 3H); 7.38 (dbr,1H); 7.21 (dd, 1H); 6.59 (dbr, 1H); 6.19 (dd, 1H). MS (ESI): [M + H]⁺ =585. 4.29

2-(3- Cyclohexylsulfamoyl- phenoxy)-4-fluoro-6- (2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 8.96 (s, 1H); 7.94(sbr, 1H); 7.84 (sbr, 1H); 7.71-7.56 (m, 4H); 7.50-7.44 (m, 2H);7.37-7.31 (m, 1H); 7.21 (dd, 1H); 6.59 (dbr, 1H); 6.12 (dbr, 1H); 2.88(m, 1H); 1.59-1.46 (m, 4H); 1.40 (m, 1H); 1.14-0.93 (m, 5H). MS (ESI):[M + H]⁺ = 628. 4.30

3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxymethyl]- piperazine-1- carboxylic acid tert- butyl ester MS(ESI): [M + H]⁺ = 589. 4.31

2-(1,4-Dimethyl- piperazin-2- ylmethoxy)-4-fluoro- 6-(2-fluoro-4-iodo-phenylamino)- benzamide MS (ESI): [M − H]⁻ = 515. 4.32

{3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-benzyl}- carbamic acid tert- butyl ester MS (ESI): [M + H]⁺ =596. 4.33

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3- sulfamoylmethyl-phenoxy)-benzamide ¹H-NMR (d₆-DMSO; 400 MHz): 9.03 (s, 1H); 7.86 (sbr,1H); 7.86 (sbr, 1H); 7.66 (dd, 1H); 7.47 (dd, 1H); 7.40 (dd, 1H); 7.20(dd, 1H); 7.18 (dbr, 1H); 7.13 (sbr, 1H); 7.09 (dd, 1H); 6.83 (s, 2H);6.53 (dbr, 1H); 6.13 (dd, 1H); 4.25 (s, 2H). MS (ESI): [M + H]⁺ = 560.4.34

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3-methane- sulfonylmethyl-phenoxy)- benzamide ¹H-NMR (d₆-DMSO; 400 MHz): 9.02 (s, 1H); 7.87 (sbr,1H); 7.86 (sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr, 1H); 7.42 (dd, 1H);7.23-7.14 (m, 3H); 7.12 (dd, 1H); 6.55 (dbr, 1H); 6.09 (dd, 1H); 4.47(s, 2H); 2.88 (s, 3H). MS (ESI): [M +H]⁺ = 559. 4.35

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(6-trifluoromethyl-pyridin-2-yloxy)- benzonitrile ¹H-NMR (d₆-DMSO; 300 MHz): 9.16 (s, 1H);8.12 (dd, 1H); 7.94 (sbr, 2H); 7.66 (d, 1H); 7.61 (dd, 1H); 7.39-7.33(m, 2H); 7.14 (dd, 1H); 6.71-6.65 (m, 2H). MS (ESI): [M +H]⁺ = 518. 4.36

5-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-nicotinic acid methyl ester ¹H-NMR: (d6-DMSO, 400 MHz) 8.88 (s,1H); 8.80 (s, 1H); 8.67 (d, 1H); 7.98 (sbr, 1H); 7.94 (sbr, 1H); 7.84(sbr, 1H); 7.66 (dd, 1H); 7.48 (dbr, 1H); 7.21 (dd, 1H); 6.59 (dbr, 1H);6.32 (dd, 1H); 3.85 (s, 3H). MS (LC-MS): [M + H]⁺ = 526. 4.37

2-(3-Carbamoyl- phenoxy)-4-fluoro- 6-(2-fluoro-4-iodo- phenylamino)-benzamide ¹H-NMR: d6-DMSO, 300 MHz) 9.03 (s, 1H); 7.99 (sbr, 1H); 7.87(sbr, 1H); 7.84 (sbr, 1H); 7.70-7.63 (m, 2H); 7.56 (sbr, 1H); 7.50-7.42(m, 3H); 7.27-7.17 (m, 2H); 6.56 (dbr, 1H); 6.11 (dd, 1H). MS (LC-MS):[M + H]⁺ = 510. 4.38

{3-[3-(4-Bromo-2- fluoro-phenylamino)- 2-carbamoyl-5- fluoro-phenoxy]-phenyl}-carbamic acid tert-butyl ester MS (LC-MS): [M + H]⁺ = 535

Example Compound 5.1 Preparation of2-{2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-ethyl}-piperidine-1-carboxylicacid dimethylamide

In analogy to GP 7, 150 mg of4-fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(2-piperidin-2-yl-ethoxy)-benzamide(0.3 mmol) were dissolved in 4.5 mL DMF and treated subsequently with 50μl triethylamine (1.2 eq.) and 33 μL dimethylcarbamoyl chloride (1.2eq.). The reaction mixture was stirred at rt for 16 h, quenched withwater, extracted with DCM, the combined organic layers were dried andconcentrated in vacuo. Flash column chromatography provided the targetcompound.

¹H-NMR: (d6-DMSO, 400 MHz): 9.70 (s, 1H); 7.77 (s, 1H); 7.72 (s, 1H);7.63 (dd, 1H); 7.44 (d, 1H); 7.18 (t, 1H); 6.41 (d, 2H); 3.93-4.02 (m,2H); 3.85-3.92 (m, 1H); 2.92 (t, 1H); 2.59 (s, 6H); 2.11-2.19 (m, 1H);1.85-1.94 (m, 1H); 1.48-1.62 (m, 5H); 1.26-1.36 (m, 1H). [one protonobscured by solvent signal]

MS (ESI): [M+H]⁺=573.

Example Compound 5.2 Preparation of2-[3-[[(propylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide

In analogy to GP 5, 422 mg of2-(3-Amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide(0.88 mmol; 1 eq.) were dissolved in 17.54 mL of DCM and treatedsubsequently with 180 μL N-Ethyl-N,N-diisopropyl amin (1.05 mmol; 1.2eq.). The solution was cooled to 0° C. for 60 Min, treated with 152.04mg propyl sulfamoyl chloride (0.96 mmol; 1.1 eq.) and stirred for 30 Minat 0° C. and 3 h at RT. Since the reaction was not completed another 0.3eq. N-Ethyl-N,N-diisopropyl amin and 0.2 eq. propyl sulfamoyl chloridewere added and the mixture stirred at RT for 48 h. The suspension wasfiltered off and the white crystals were washed with DCM and dried toafford 469 mg of the pure target compound (89% yield, 0.78 mmol).

¹H-NMR (d₆-DMSO; 300 MHz): 9.80 (s, 1H); 9.10 (s, 1H); 7.85 (sbr, 1H);7.82 (sbr, 1H); 7.66 (dd, 1H); 7.51-7.44 (m, 2H); 7.28 (dd, 1H); 7.20(dd, 1H); 6.95 (dd, 1H); 6.90 (dd, 1H); 6.71 (dd, 1H); 6.53 (ddd, 1H);6.00 (dd, 1H); 2.74 (dt, 2H); 1.32 (q, 2H); 0.71 (t, 3H).

MS (ESI): [M+H]⁺=603

Example Compound 5.3 Preparation of2-(3-Acetylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide

In analogy to GP 8, 96.25 mg of2-(3-Amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide(0.2 mmol; 1 eq.) were dissolved in 5 mL of DCM, treated with 41.08 μLN-Ethyl-N,N-diisopropyl amin (0.24 mmol; 1.2 eq.). Upon cooling to 0°C., 0.014 ml of acetyl chloride (0.2 mmol; 1.01 eq.) were added themixture stirred at 3° C. for 1 h and at RT for 23 h. The suspension wasfiltered off and the precipitate was washed with DCM and dried to afford65 mg of the pure target compound (62% yield, 0.12 mmol).

¹H-NMR (d₆-DMSO; 400 MHz): 10.02 (s, 1H); 9.09 (s, 1H); 7.85 (sbr, 1H);7.83 (sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr, 1H); 7.38 (sbr, 1H); 7.33-7.25(m, 2H); 7.21 (dd, 1H); 6.73 (ddd, 1H); 6.56 (dbr, 1H); 6.11 (dd, 1H);1.99 (t, 3H).

MS (ESI): [M+H]⁺=524

The following example compounds 5.4 to 5.89 were prepared in analogy toexample compounds 5.1a to 5.4 by applying GP 5 (for sulfamides), GP 6(for sulfonamides), GP 7 (for ureas) or GP 8a and 8 b (for amides) tothe respective amines.

Ex- am- ple Structure Name Analytical data 5.4

2-[3-(3-Chloro- propane-1- sulfonylamino)- phenoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 400 MHz)10.04 (s, 1H); 9.01 (s, 1H); 7.87 (sbr, 1H); 7.83 (sbr, 1H); 7.66 (dd,1H); 7.47 (dbr, 1H); 7.33 (dd, 1H); 7.20 (dd, 1H); 6.99 (dbr, 1H); 6.94(dd, 1H); 6.79 (dd, 1H); 6.56 (dbr, 1H); 6.12 (dd, 1H); 3.68 (t, 2H);3.31-3.21 (m, 2H); 2.06 (tt, 2H). MS (ESI): [M + H]⁺ = 622 5.5

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3-bis- methanesulfonyl-amino-phenoxy)- benzamide MS (ESI): [M + H]+ = 638 5.6

2-[3-(1,1-Dioxo-1λ⁶- isothiazolidin-2-yl)- phenoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz)9.01 (s, 1H); 7.87 (sbr, 1H); 7.86 (sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr,1H); 7.37 (dd, 1H); 7.21 (dd, 1H); 7.04- 6.96 (m, 2H); 6.77 (dd, 1H);6.54 (dbr, 1H); 6.04 (dd, 1H); 3.71 (t, 2H); 3.50 (t, 2H); 2.36 (tt,2H). MS (ESI): [M + H]⁺ = 586 5.7

2-[3- [[(amino)sulfonyl] amino]phenoxy]-4- fluoro-6-[(2-fluoro-4-iodophenyl)amino]- benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 9.66 (s, 1H);9.11 (s, 1H); 7.85 (sbr, 1H); 7.80 (sbr, 1H); 7.66 (dd, 1H); 7.47 (dd,1H); 7.27 (dd, 1H); 7.20 (dd, 1H); 7.14 (sbr, 2H); 6.95 (dd, 1H); 6.90(dd, 1H); 6.68 (dd, 1H); 6.54 (dd, 1H); 6.05 (dd, 1H). MS (ESI): [M +H]⁺ = 561 5.8

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3-formylamino-phenoxy)-benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 10.28 (s, 1H); 9.07 (s,1H); 8.24 (d, 1H); 7.86 (sbr, 1H); 7.83 (sbr, 1H); 7.66 (dd, 1H); 7.47(dbr, 1H); 7.32 (d, 1H); 7.21 (dd, 1H); 6.77 (m, 1H); 6.56 (dbr, 1H);6.12 (dd, 1H). MS (ESI): [M + H]⁺ = 510 5.9

2-[2-(1- Ethanesulfonyl- piperidin-2-yl)- ethoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz)9.73 (s, 1H); 7.81 (s, 1H); 7.68 (dd, 1H); 7.62 (s, 1H); 7.49 (d, 1H);7.23 (t, 1H); 6.44-6.50 (m, 2H); 3.98- 4.13 (m, 3H); 3.51-3.58 (m, 1H);3.00-3.12 (m, 3H); 2.18-2.30 (m, 1H); 1.97- 2.07 (m, 1H); 1.55-1.72 (m,5H); 1.36-1.52 (m, 1H); 1.18 (t, 3H). 5.10

2-(3-Benzene- sulfonylamino- propoxy)-4-fluoro- 6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.47 (s, 1H);7.56-7.83 (m, 9H); 7.49 (d, 1H); 7.21 (t, 1H); 6.46 (s, 1H); 6.42 (s,1H); 4.03 (t, 2H); 2.93 (q, 2H); 1.85 (m, 2H). MS (ESI): [M + H]⁺ = 588.5.11

2-(3-Benzoylamino- propoxy)-4-fluoro-6- (2-fluoro-4-iodo- phenylamino)-benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.61 (s, 1H); 8.59 (t, 1H);7.81-7.89 (m, 4H); 7.68 (dd, 1H); 7.44-7.56 (m, 4H); 7.23 (t, 1H);6.44-6.54 (m, 2H); 4.08 (t, 2H); 3.47 (q, 2H); 2.01 (m, 2H). MS (ESI):[M + H]⁺ = 552. 5.12

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(3-phenyl-ureido)-propoxy]- benzamide MS (ESI): [M + H]⁺ = 567. 5.13

2-(1-Benzenesulfonyl- piperidin-3- ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz)9.33 (s, 1H); 7.79 (br. s, 1H); 7.57-7.73 (m, 7 H); 7.45 (d, 1H); 7.16(t, 1H); 6.38- 6.49 (m, 2H); 3.85-3.91 (m, 2H); 3.59-3.64 (m, 1H);3.41-3.47 (m, 1H); 2.00- 2.37 (m, 3H); 1.62-1.74 (m, 2H); 1.39-1.54 (m,1H); 0.98-1.12 (m, 1H); MS (ESI): [M + H]⁺ = 628. 5.14

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(1- methanesulfonyl-piperidin-3- ylmethoxy)- benzamide MS (ESI): [M + H]⁺ = 566. 5.15

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(pyridin-3-ylmethanesulfonyl- amino)-propoxy]- benzamide MS (ESI): [M + H]⁺ = 603.5.16

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(1-methyl-1H-imidazole-4- sulfonylamino)- propoxy]-benzamide MS (ESI): [M + H]⁺ =592. 5.17

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(1-methyl-1H-pyrazole-4- sulfonylamino)- propoxy]-benzamide MS (ESI): [M + H]⁺ = 592.5.18

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3-trifluoro-methanesulfonyl- amino-propoxy)- benzamide MS (ESI): [M + H]⁺ = 580.5.19

2-(1-Ethanesulfonyl- piperidin-3- ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide MS (ESI): [M + H]⁺ = 580.5.20

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[2-(1- methanesulfonyl-piperidin-2-yl)- ethoxy]-benzamide ¹H-NMR: (d6-DMSO, 400 MHz) 9.68 (s,1H); 7.76 (br. s, 1H); 7.63 (dd, 1H); 7.55 (br. s, 1H); 7.44 (d, 1H);7.19 (t, 1H); 6.40-6.44 (m, 2H); 3.95- 4.05 (m, 3H); 3.56 (br. d, 1H);3.01 (br. t, 1H); 2.91 (s, 3H); 2.17-2.26 (m, 1H); 1.87-1.96 (m, 1H);1.37- 1.71 (m, 6H). MS (ESI): [M + H]⁺ = 580. 5.21

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(1- methanesulfonyl-pyrrolidin-3- ylmethoxy)- benzamide MS (ESI): [M + H]⁺ = 552. 5.22

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(1- methanesulfonyl-piperidin-4-yloxy)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.20 (s, 1H);7.79 (br. s, 1H); 7.63 (dd, 1H); 7.59 (br. s, 1H); 7.44 (d, 1H); 7.16(t, 1H); 6.59 (dd, 1H); 6.40 (dd, 1H); 4.61-4.67 (m, 1H); 3.20- 3.30 (m,2H); 3.08-3.17 (m, 2H); 2.85 (s, 3H); 1.91-2.01 (m, 2H); 1.75-1.86 (m,2H). MS (ESI): [M + H]⁺ = 552. 5.23

4-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-piperidine- 1-carboxylic acid dimethylamide ¹H-NMR: (d6-DMSO,400 MHz) 9.46 (s, 1H); 7.78 (br. s, 1H); 7.63 (dd, 1H); 7.58 (br. s,1H); 7.44 (d, 1H); 7.17 (t, 1H); 6.59 (dd, 1H); 6.39 (dd, 1H); 4.60-4.67(m, 1H); 2H obscured by solvent signal; 2.95-3.06 (m, 2H); 2.70 (s, 6H);1.86-1.94 (m, 2H); 1.60-1.69 (m, 2H). MS (ESI): [M + H]⁺ = 545. 5.24

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(morpholine-4-sulfonylamino)- phenoxy]-benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 10.15 (s,1H); 9.06 (s, 1H); 7.87 (sbr, 1H); 7.83 (sbr, 1H); 7.66 (dd, 1H); 7.47(dd, 1H); 7.30 (dd, 1H); 7.20 (dd, 1H); 6.96 (dd, 1H); 6.91 (dd, 1H);6.77 (dd, 1H); 6.57 (dd, 1H); 6.12 (dd, 1H); 3.48 (dd, 4H); 3.02 (dd,4H). MS (ESI): [M + H]⁺ = 631. 5.25

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[1-(1H-imidazole-4-sulfonyl)-azetidin-3- ylmethoxy]- benzamide MS (ESI): [M + H]⁺ = 590.5.26

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(1- methanesulfonyl-azetidin-3- ylmethoxy)- benzamide MS (ESI): [M + H]⁺ = 538. 5.27

2-[2-(1- Cyclopropanesulfonyl- piperidin-2-yl)- ethoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz)9.70 (s, 1H); 7.79 (br. s, 1H); 7.63 (dd, 1H); 7.53 (br. s, 1H); 7.44(d, 1H); 7.19 (t, 1H); 6.40-6.44 (m, 2H); 3.95- 4.07 (m, 3H); 3.51-3.57(m, 1H); 3.00-3.05 (m, 1H); 2.57-2.63 (m, 1H); 2.19- 2.30 (m, 1H);1.85-1.96 (m, 1H); 1.58-1.80 (m, 1H); 1.45-1.64 (m, 5H); 0.87- 0.96 (m,4H). MS (ESI): [M + H]⁺ = 606. 5.28

2-(1-Acetyl-piperidin- 4-yloxy)-4-fluoro-6- (2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.39 (s, 1H); 7.78(br. s, 1H); 7.63 (dd, 1H); 7.58 (br. s, 1H); 7.45 (d, 1H); 7.17 (t,1H); 6.60 (dd, 1H); 6.40 (dd, 1H); 4.65-4.73 (m, 1H); 3.54- 3.73 (m,2H); 3.25-3.37 (m, 2H); 1.98 (s, 3H); 1.79-1.94 (m, 2H); 1.52-1.75 (m,2H). MS (ESI): [M + H]⁺ = 516. 5.29

4-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-piperidine- 1-carboxylic acid ethyl ester ¹H-NMR: (d6-DMSO, 400MHz) 9.37 (s, 1H); 7.77 (br. s, 1H); 7.63 (dd, 1H); 7.57 (br. s, 1H);7.44 (d, 1H); 7.16 (t, 1H); 6.59 (dd, 1H); 6.40 (dd, 1H); 4.63-4.69 (m,1H); 4.01 (q, 2H); 3.54-3.60 (m, 2H); 3.23-3.29 (m, 2H); 1.83- 1.91 (m,2H); 1.58-1.67 (m, 2H); 1.15 (t, 3H). MS (ESI): [M + H]⁺ = 546. 5.30

4-{2-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-ethyl}- piperazine-1- carboxylic acid dimethylamide ¹H-NMR:(d6-DMSO, 400 MHz) 10.67 (s, 1H); 8.44 (s, 1H); 7.79 (s, 1H); 7.65 (d,1H); 7.47 (d, 1H); 7.22 (t, 1H); 6.49 (d, 1H); 6.39 (d, 1H); 4.16-4.22(m, 2H); 3.05- 3.10 (m, 4H); 2.69 (s, 6H); 2.65-2.69 (m, 2H); 2.38- 2.42(m, 4H). MS (ESI): [M + H]⁺ = 574. 5.31

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[2-(4- methanesulfonyl-piperazin-1-yl)- ethoxy]-benzamide ¹H-NMR: (d6-DMSO, 400 MHz) 10.68 (s,1H); 8.46 (s, 1H); 7.82 (s, 1H); 7.65 (dd, 1H); 7.47 (d, 1H); 7.22 (t,1H); 6.50 (dd, 1H); 6.39 (d, 1H); 4.20 (t, 2H); 3.04-3.08 (m, 4H); 2.84(s, 3H); 2.72 (t, 2H); 2.50-2.54 (m, 4H). 5.32

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-((R)-1- methanesulfonyl-pyrrolidin-2- ylmethoxy)- benzamide ¹H-NMR: (d6-DMSO, 400 MHz) 9.54 (s,1H); 7.80 (br. s, 1H); 7.68 (br. s, 1H); 7.63 (dd, 1H); 7.45 (br d, 1H);7.17 (t, 1H); 6.50 (dd, 1H); 6.42 (dd, 1H); 4.00-4.10 (m, 2H); 3.93 (t,1H); 3.26 (m, 2H); 2.94 (s, 3H); 1.76-2.03 (m, 4H). MS (ESI): [M + H]⁺ =552. 5.33

2-((R)-1- Ethanesulfonyl- pyrrolidin-2- ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 400 MHz)9.51 (s, 1H); 7.80 (br. s, 1H); 7.68 (br. s, 1H); 7.63 (dd, 1H); 7.45(br d, 1H); 7.17 (t, 1H); 6.51 (dd, 1H); 6.41 (dd, 1H); 4.05-4.12 (m,2H); 3.93 (dd, 1H); 3.21-3.37 (m, 2H); 3.04 (q, 3H); 1.77- 2.01 (m, 4H);1.19 (t, 3H). MS (ESI): [M + H]⁺ = 566. 5.34

2-((S)-1- Ethanesulfonyl- pyrrolidin-2- ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 400 MHz)9.51 (s, 1H); 7.80 (br. s, 1H); 7.68 (br. s, 1H); 7.63 (dd, 1H); 7.45(br d, 1H); 7.17 (t, 1H); 6.50 (dd, 1H); 6.42 (dd, 1H); 4.05-4.12 (m,2H); 3.93 (dd, 1H); 3.22-3.36 (m, 2H); 3.12 (q, 3H); 1.76- 2.04 (m, 4H);1.19 (t, 3H). MS (ESI): [M + H]⁺ = 566. 5.35

2-(4- dimethylsulfamoyl- amino-cyclohexyloxy)- 4-Fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.74 (s, 1H);7.74 (br. s, 1H); 7.63 (dd, 1H); 7.54 (br s, 1H); 7.45 (d, 1H); 7.14-7.20 (m, 2H); 6.57 (dd, 1H); 6.37 (dd, 1H); 4.29-4.40 (m, 1H); 3.01-3.12(m, 1H); 2.61 (s, 6H); 1.99-2.09 (m, 2H); 1.83-1.93 (m, 2H); 1.32-1.55(m, 4H). 5.36

2-(3- Cyclopropanesulfonyl amino-phenoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.87 (s, 1H);9.04 (s, 1H); 7.88 (br s, 1H); 7.84 (br s, 1H); 7.66 (dd, 1H); 7.47 (brd, 1H); 7.31 (t, 1H); 7.21 (t, 1H); 7.00 (dd, 1H); 6.96 (s, 1H); 6.77(dd, 1H); 6.57 (dd, 1H); 6.13 (dd, 1H); 2.63 (m, 1H); 0.80-0.92 (m, 4H).MS (ESI): [M + H]⁺ = 586. 5.37

2-(3- Cyclopentanesulfonyl amino-phenoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.85 (s, 1H);9.02 (s, 1H); 7.87 (br s, 1H); 7.84 (br s, 1H); 7.66 (dd, 1H); 7.47 (brd, 1H); 7.31 (t, 1H); 7.20 (t, 1H); 6.99 (dd, 1H); 6.94 (t, 1H); 6.76(dd, 1H); 6.57 (dd, 1H); 6.13 (dd, 1H); 3.55 (m, 1H); 1.77-1.87 (m, 4H);1.45- 1.67 (m, 4H). MS (ESI): [M + H]⁺ = 614. 5.38

2-(3- diethylsulfamoyl- amino-phenoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.92 (s, 1H);9.09 (s, 1H); 7.86 (br s, 1H); 7.83 (br s, 1H); 7.66 (dd, 1H); 7.47 (brd, 1H); 7.29 (t, 1H); 7.20 (t, 1H); 6.88 (dd, 1H); 6.80 (s, 1H); 6.75(dd, 1H); 6.55 (dd, 1H); 6.05 (dd, 1H); 3.19 (q, 4H); 0.92 (t, 6H). MS(ESI): [M + H]⁺ = 617. 5.39

2-((R)-1-Acetyl- pyrrolidin-2- ylmethoxy)-4-fluoro- 6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 400 MHz) 9.59 (s, 1H); 7.78(br. s, 1H); 7.75 (br. s, 1H); 7.65 (dd, 1H); 7.48 (br d, 1H); 7.17 (t,1H); 6.61 (dd, 1H); 6.42 (dd, 1H); 4.24-4.35 (m, 1H); 4.14 (dd, 1H);4.03 (dd, 1H); 3.37-3.53 (m, 2H); 1.97 (s, 3H); 1.79-2.07 (m, 4H). MS(ESI): [M + H]⁺ = 516. 5.40

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(pyrrolidine-1-sulfonylamino)- phenoxy]-benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.96 (s,1H); 9.07 (s, 1H); 7.86 (br s, 1H); 7.83 (br s, 1H); 7.66 (dd, 1H); 7.47(d, 1H); 7.28 (t, 1H); 7.21 (t, 1H); 6.95 (d, 1H); 6.88 (s, 1H); 6.75(dd, 1H); 6.57 (dd, 1H); 6.09 (dd, 1H); 3.11 (t, 4H); 1.69 (t, 4H). MS(ESI): [M + H]⁺ = 615. 5.41

2-[3- [[(methylamino) sulfonyl]amino] phenoxy]-4-fluoro- 6-[(2-fluoro-4-iodophenyl)amino]- benzamide ¹H-NMR: (d6-DMSO, 400 MHz) 9.83 (s, 1H);9.06 (s, 1H); 7.86 (br s, 1H); 7.82 (br s, 1H); 7.66 (dd, 1H); 7.47 (d,1H); 7.35 (br q, 1H); 7.27 (t, 1H); 7.20 (t, 1H); 6.95 (d, 1H); 6.90 (s,1H); 6.69 (dd, 1H); 6.54 (dd, 1H); 6.07 (dd, 1H); 2.42 (d, 3H). 5.42

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[(R)-1-(imidazole-1-carbonyl)-pyrrolidin- 2-ylmethoxy]- benzamide ¹H-NMR: (d6-DMSO, 300 MHz)9.24 (s, 1H); 8.06 (s, 1H); 7.83 (br. s, 1H); 7.77 (br. s, 1H); 7.63(dd, 1H); 7.49 (s, 1H); 7.44 (dd, 1H); 7.14 (t, 1H); 6.98 (s, 1H); 6.53(dd, 1H); 6.39 (dd, 1H); 4.38- 4.45 (m, 1H); 4.15-4.23 (m, 2H);3.60-3.68 (m, 1H); 3.50-3.58 (m, 1H); 2.05-2.14 (m, 1H); 1.90-2.02 (m,2H); 1.72-1.90 (m, 1H). 5.43

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[(S)-1-(imidazole-1-carbonyl)-pyrrolidin- 2-ylmethoxy]- benzamide ¹H-NMR: (d6-DMSO, 300 MHz)9.24 (s, 1H); 8.06 (s, 1H); 7.83 (br. s, 1H); 7.77 (br. s, 1H); 7.62(dd, 1H); 7.49 (s, 1H); 7.44 (dd, 1H); 7.14 (t, 1H); 6.98 (s, 1H); 6.53(dd, 1H); 6.39 (dd, 1H); 4.38-4.45 (m, 1H); 4.15-4.25 (m, 2H); 3.61-3.69(m, 1H); 3.50- 3.57 (m, 1H); 2.05-2.14 (m, 1H); 1.90-2.02 (m, 2H);1.72-1.90 (m, 1H). 5.44

2-(1-Acetyl-azetidin- 3-ylmethoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide MS (ESI): [M + H]⁺ = 502. 5.45

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(4- methanesulfonyl-morpholin-2- ylmethoxy)- benzamide MS (ESI): [M + H]⁺ = 568. 5.46

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(4- methanesulfonyl-morpholin-2- ylmethoxy)- benzamide MS (ESI): [M + H]⁺ = 568. 5.47

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(4H- [1,2,4]triazole-3-sulfonylamino)- phenoxy]-benzamide ¹H-NMR (d₆-DMSO; 400 MHz): 14.82 (s,1H); 10.89 (s, 1H); 9.00 (s, 1H); 8.47 (s, 1H); 7.84 (sbr, 1H); 7.81(sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr, 1H); 7.25 (dd, 1H); 7.20 (dd, 1H);6.96 (ddd, 1H); 6.91 (sbr, 1H); 6.73 (dd, 1H); 6.54 (dd, 1H); 5.97 (dd,1H). MS (ESI): [M + H]⁺ = 613. 5.48

2-(3- Cyclobutanesulfonyl- amino-phenoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR (d₆-DMSO; 400 MHz): 9.56 (sbr, 1H);9.02 (s, 1H); 7.87 (sbr, 1H); 7.84 (sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr,1H); 7.29 (dd, 1H); 7.21 (dd, 1H); 6.96 (dbr, 1H); 6.91 (dd, 1H); 6.75(dd, 1H); 6.57 (dbr, 1H); 6.13 (dd, 1H); 3.93 (dt, 1H); 2.27 (m, 2H);2.12 (m, 2H); 1.94-1.77 (m, 2H). MS (ESI): [M + H]⁺ = 600. 5.49

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(1H-imidazole-4-sulfonylamino)- phenoxy]-benzamide ¹H-NMR (d₆-DMSO; 300 MHz): 12.72(sbr, 1H); 10.37 (sbr, 1H); 9.06 (s, 1H); 7.83 (sbr, 1H); 7.81 (sbr,1H); 7.76 (s, 2H); 7.66 (dd, 1H); 7.47 (dbr, 1H); 7.20 (m, 2H); 6.93(dbr, 1H); 6.89 (sbr, 1H); 6.67 (dd, 1H); 6.54 (dbr, 1H); 5.94 (dd, 1H).MS (ESI): [M + H]⁺ = 612. 5.50

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(1- methanesulfonyl-pyrrolidin-3- ylmethoxy)- benzamide t_(R) = 6.38 (HPLC conditions C); MS(ESI): [M + H]⁺ = 552. 5.51

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(1- methanesulfonyl-pyrrolidin-3- ylmethoxy)- benzamide t_(R) = 7.55 (HPLC conditions C); MS(ESI): [H + M]⁺ = 552. 5.52

2-[3-[[(di-2- methoxyethylyl- amino)sulfonyl] amino]phenoxy]-4-fluoro-6- [(2-fluoro-4- iodophenyl)amino]- benzamide MS (ESI): [M +H]⁺ = 677. 5.53

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[1-(morpholine-4-sulfonyl)-pyrrolidin- 3-ylmethoxy]- benzamide t_(R) = 4.74 (HPLCconditions C); MS (ESI): [M + H]⁺ = 623. 5.54

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[1-(morpholine-4-sulfonyl)-pyrrolidin-3- ylmethoxy]- benzamide t_(R) = 5.51 (HPLCconditions C); MS (ESI): [M + H]⁺ = 623. 5.55

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[1-(1H-imidazole-4-sulfonyl)-piperidin-3- ylmethoxy]- benzamide MS (ESI): [M + H]⁺ = 618.5.56

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[1-(4H- [1,2,4]triazole-3-sulfonyl)-piperidin- 3-ylmethoxy]- benzamide MS (ESI): [M + H]⁺ = 619.5.57

2-(1-Acetyl-piperidin- 3-ylmethoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide t_(R) = 6.92 (HPLC conditions C, withbuffer: hexane/0.1% DEA); MS (ESI): [M + H]⁺ = 530. 5.58

2-(1-Acetyl-piperidin- 3-ylmethoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide t_(R) = 8.75 (HPLC conditions C, withbuffer: hexane/0.1% DEA); MS (ESI): [M + H]⁺ = 530. 5.59

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[1-(1-methyl-1H-pyrazole-4-sulfonyl)- azetidin-3- ylmethoxy]- benzamide MS (ESI): [M +H]⁺= 604. 5.60

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[1-(1-methyl-1H-imidazole-4-sulfonyl)- azetidin-3- ylmethoxy]- benzamide MS (ESI): [M +H]⁺ = 604. 5.61

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(1-methyl-1H-pyrazole-4- sulfonylamino)- phenoxy]-benzamide ¹H-NMR (d₆-DMSO; 400MHz): 10.26 (sbr, 1H); 9.02 (s, 1H); 8.18 (s, 1H); 7.86 (sbr, 1H); 7.82(sbr, 1H); 7.66 (dd, 1H); 7.65 (s, 1H); 7.47 (dbr, 1H); 7.25 (dd, 1H);7.20 (dd, 1H); 6.90 (dbr, 1H); 6.85 (dd, 1H); 6.73 (dd, 1H); 6.56 (dbr,1H); 6.00 (dd, 1H); 3.79 (s, 3H). MS (ESI): [M + H]⁺ = 626. 5.62

2-[3-(1,1-Dioxo- tetrahydro-1λ⁶- thiophene-3- sulfonylamino)-phenoxy]-4-fluoro-6- (2-fluoro-4-iodo- phenylamino)- benzamide ¹H-NMR(d₆-DMSO; 300 MHz): 10.32 (s, 1H); 8.96 (s, 1H); 7.88 (sbr, 1H); 7.85(sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr, 1H); 7.35 (dd, 1H); 7.20 (dd, 1H);7.01 (dbr, 1H); 6.96 (dd, 1H); 6.82 (dd, 1H); 6.56 (dbr, 1H); 6.18 (dd,1H); 4.19 (dt, 1H); 3.47 (dd, 1H); 3.34-3.11 (m, 3H); 2.51-2.25 (m, 2H).MS (ESI): [M + H]⁺ = 664. 5.63

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[1-(1-methyl-1H-imidazole-4-sulfonyl)- piperidin-3- ylmethoxy]- benzamide MS (ESI): [M−H]⁻ = 630. 5.64

3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxymethyl]-4- methanesulfonyl- piperazine-1- carboxylic acid tert-butyl ester MS (ESI): [M + H]⁺ = 667. 5.65

3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxymethyl]- pyrrolidine-l-sulfonic acid MS (ESI): [M + H]⁺ = 554.5.66

6-[3- (aminosulfonylamino- methyl)-phenoxy]-4- fluoro-2-(2-fluoro-4-iodo-phenylamino)-6- benzamide ¹H-NMR (d₆-DMSO; 400 MHz): 9.08 (s, 1H);7.86 (sbr, 1H); 7.84 (sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr, 1H); 7.35 (dd,1H); 7.21 (dd, 1H); 7.17 (dbr, 1H); 7.13 (sbr, 1H); 7.09 (dd, 1H); 6.98(ddd, 1H); 6.62 (s, 2H); 6.52 (dbr, 1H); 6.00 (dd, 1H); 4.05 (d, 2H). MS(ESI): [M + H]⁺ = 575. 5.67

6-[3-(dimethyl- aminosulfonylamino- methyl)-phenoxy]- 4-fluoro-2-(2-fluoro-4-iodo- phenylamino)-6- benzamide ¹H-NMR (d₆-DMSO; 400 MHz):9.07 (s, 1H); 7.85 (sbr, 2H); 7.71 (dd, 1H); 7.66 (dd, 1H); 7.47 (dbr,1H); 7.37 (dd, 1H); 7.21 (dd, 1H); 7.15 (dbr, 1H); 7.09 (sbr, 1H); 7.00(dd, 1H); 6.54 (dbr, 1H); 6.03 (dd, 1H); 4.08 (d, 2H); 2.58 (s, 6H). MS(ESI): [M + H]⁺ = 603. 5.68

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[3-(methane- sulfonylamino-methyl)-phenoxy]- benzamide ¹H-NMR (d₆-DMSO; 400 MHz): 9.06 (s, 1H);7.86 (sbr, 1H); 7.85 (sbr, 1H); 7.66 (dd, 1H); 7.57 (dd, 1H); 7.47 (dbr,1H); 7.37 (dd, 1H); 7.21 (dd, 1H); 7.15 (dbr, 1H); 7.10 (sbr, 1H); 7.00(dd, 1H); 6.54 (dbr, 1H); 6.03 (dd, 1H); 4.13 (d, 2H); 2.83 (s, 3H). MS(ESI): [M + H]⁺ = 574. 5.69

2-[3-(Acetylamino- methyl)-phenoxy]-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR (d₆-DMSO; 400 MHz): 9.07 (s, 1H);8.34 (dd, 1H); 7.85 (sbr, 2H); 7.66 (dd, 1H); 7.47 (dbr, 1H); 7.34 (dd,1H); 7.21 (dd, 1H); 7.06 (dbr, 1H); 7.01 (sbr, 1H); 6.95 (dd, 1H); 6.53(dbr, 1H); 6.00 (dd, 1H); 4.22 (d, 2H); 1.83 (s, 3H). 5.70

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[4-(1-methyl-1H-imidazole-4-sulfonyl)- morpholin-2- ylmethoxy]- benzamide t_(R) = 8.44(HPLC conditions C, but 100% methanole, PDA: 280 nm); MS (ESI): [M + H]⁺= 634. 5.71

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[4-(1-methyl-1H-imidazole-4-sulfonyl)- morpholin-2- ylmethoxy]- benzamide t_(R) = 12.60(HPLC conditions C, but 100% methanole, PDA: 280 nm); MS (ESI): [M + H]⁺= 634. 5.72

2-[3-(2,2-Dimethyl- propionylamino)- phenoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide t_(R) = 1.50 (HPLC conditionsA); MS (ESI): [M + H]⁺ = 565. 5.73

2-[3-(Cyclo- propanecarbonyl- amino)-phenoxy]- 4-fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide t_(R) = 1.42 (HPLC conditions A); MS(ESI): [M + H]⁺ = 549. 5.74

2-[3-(Cyclo- pentanecarbonyl- amino)-phenoxy]- 4-fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide t_(R) = 1.52 (HPLC conditions A); MS(ESI): [M + H]⁺ = 577. 5.75

Thiophene-3- carboxylic acid {3-[2- carbamoyl-5-fluoro-3-(2-fluoro-4-iodo- phenylamino)- phenoxy]-phenyl}- amide t_(R) = 1.46(HPLC conditions A); MS (ESI): [M + H]⁺ = 590. 5.76

[1,2,3]Thiadiazole-4- carboxylic acid {3-[2- carbamoyl-5-fluoro-3-(2-fluoro-4-iodo- phenylamino)- phenoxy]-phenyl}- amide t_(R) = 1.42(HPLC conditions A); MS (ESI): [M + H]⁺ = 592. 5.77

Furan-3-carboxylic acid {3-[2-carbamoyl- 5-fluoro-3-(2-fluoro-4-iodo-phenylamino)- phenoxy]-phenyl}- amide t_(R) = 1.42 (HPLCconditions A); MS (ESI): [M + H]⁺ = 575. 5.78

Isoxazole-5- carboxylic acid {3-[2- carbamoyl-5-fluoro-3-(2-fluoro-4-iodo- phenylamino)- phenoxy]-phenyl}- amide t_(R) = 1.39(HPLC conditions A); MS (ESI): [M + H]⁺ = 576. 5.79

1H-Pyrazole-4- carboxylic acid {3-[2- carbamoyl-5-fluoro-3-(2-fluoro-4-iodo- phenylamino)- phenoxy]-phenyl}- amide t_(R) = 1.28(HPLC conditions A); MS (ESI): [M + H]⁺ = 575. 5.80

2-[3-(Cyclo- butanecarbonyl- amino)-phenoxy]-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide t_(R) = 1.47 (HPLC conditions A); MS (ESI):[M + H]⁺ = 563. 5.81

1H-Pyrazole-3- carboxylic acid {3-[2- carbamoyl-5-fluoro-3-(2-fluoro-4-iodo- phenylamino)- phenoxy]-phenyl}- amide t_(R) = 1.34(HPLC conditions A); MS (ESI): [M + H]⁺ = 575. 5.82

3-Methyl-3H- imidazole-4- carboxylic acid {3-[2- carbamoyl-5-fluoro-3-(2-fluoro-4-iodo- phenylamino)- phenoxy]-phenyl}- amide t_(R) = 1.32(HPLC conditions A); MS (ESI): [M + H]⁺ = 589. 5.83

3-Methyl-isoxazole-4- carboxylic acid {3-[2- carbamoyl-5-fluoro-3-(2-fluoro-4-iodo- phenylamino)- phenoxy]-phenyl}- amide t_(R) = 1.42(HPLC conditions A); MS (ESI): [M + H]⁺ = 590. 5.84

Isoxazole-3- carboxylic acid {3-[2- carbamoyl-5-fluoro-3-(2-fluoro-4-iodo- phenylamino)- phenoxy]-phenyl}- amide t_(R) = 1.42(HPLC conditions A); MS (ESI): [M + H]⁺ = 576. 5.85

N-{3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-phenyl}- isonicotinamide t_(R) = 1.33 (HPLC conditions A); MS(ESI): [M + H]⁺ = 587. 5.86

2-[3-(2-Chloro- propane-2- sulfonylamino)- phenoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide ¹H-NMR (d₆-DMSO; 600 MHz):9.13 (s, 1H); 8.68 (s, 1H); 7.89 (sbr, 2H); 7.69 (dd, 1H); 7.51 (dbr,1H); 7.31 (dd, 1H); 7.25 (dd, 1H); 6.92 (dbr, 1H); 6.87 (dd, 1H); 6.69(dd, 1H); 6.60 (dbr, 1H); 6.19 (dd, 1H); 1.81 (s, 3H); 1.80 (s, 3H). MS(ESI): [M + H]⁺ = 622. 5.87

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[4-(1-methyl-1H-pyrazole-4-sulfonyl)- morpholin-2- ylmethoxy]- benzamide t_(R) = 8.89(HPLC conditions C); MS (ESI): [M + H]⁺ = 634. 5.88

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[4-(1-methyl-1H-pyrazole-4-sulfonyl)- morpholin-2- ylmethoxy]- benzamide t_(R) = 10.20(HPLC conditions C); MS (ESI): [M + H]⁺ = 634. 5.89

1-Methyl-1H-pyrrole- 2-carboxylic acid {3- [2-carbamoyl-5-fluoro-3-(2-fluoro-4- iodo-phenylamino)- phenoxy]-phenyl}- amide t_(R) =1.49 (HPLC conditions A); MS (ESI): [M + H]⁺ = 589.

Example Compound 5.90 Preparation of4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-isobutyrylamino-phenoxy)-benzamide

240 mg of2-(3-amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide(0.5 mmol, 1 eq.) were dissolved in 5 mL EtOAc and treated subsequentlywith 0.27 mL N-methyl morpholine (2.5 mmol, 5 eq.), 0.42 mL T3P (0.6mmol, 1.2 eq.) and 43 μL isopropyl carboxylic acid (0.52 mmol, 1.05eq.). The resulting mixture was stirred at rt for 16 h. The mixture wasdiluted with EtOAc, quenched with aq. NaHCO₃ solution, dried andconcentrated in vacuo. The residue was triturated to yield 232 mg (84%yield) of the pure product as a white solid.

¹H-NMR: (d6-DMSO, 400 MHz) 9.91 (s, 1H); 9.11 (s, 1H); 7.84 (br s, 2H);7.66 (dd, 1H); 7.47 (dd, 1H); 7.42 (t, 1H); 7.35 (br d, 1H); 7.28 (t,1H); 7.21 (t, 1H); 6.73 (ddd, 1H); 6.56 (dd, 1H); 6.12 (dd, 1H); 2.53(sept, 1H); 1.04 (d, 6H).

MS (ESI): [M+H]⁺=552.

The following example compounds 5.91 to 5.105 were prepared in analogyto example compounds 5.1a to 5.4 by applying GP 5 (for sulfamides), GP 6(for sulfonamides), GP 7 (for ureas) or GP 8a and 8 b (for amides) tothe respective amines.

Ex- am- ple Structure Name Analytical data 5.91

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-{3-[(1-hydroxy-cyclopropane- carbonyl)-amino]- phenoxy}-benzamide MS (ESI): [M + H]+ =566. 5.92

2-[5-(1,1-Dioxo- tetrahydro-1λ⁶- thiophene-3- sulfonylamino)-pyridin-3-yloxy]-4- fluoro-6-(2-fluoro-4- iodo-phenylamino)- benzamide¹H-NMR: (d6-DMSO, 400 MHz) 10.63 (sbr, 1H); 8.83 (s, 1H); 8.24 (d, 1H);8.17 (d, 1H); 7.96 (sbr, 1H); 7.86 (sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr,1H); 7.37 (dd, 1H); 7.20 (dd, 1H); 6.58 (dbr, 1H); 6.30 (dd, 1H); 4.27(dt, 1H); 3.53 (dd, 1H); 3.35-3.26 (m, 1H); 3.24-3.12 (m, 2H); 2.53-2.39(m, 1H); 2.29 (m, 1H). MS (LC-MS): [M + H]⁺ = 665. 5.93

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[5-(1H-imidazole-4-sulfonylamino)- pyridin-3-yloxy]- benzamide ¹H-NMR: (d6-DMSO, 400 MHz)12.80 (s, 1H); 10.66 (sbr, 1H); 8.91 (s, 1H); 8.15 (d, 1H); 8.01 (d,1H); 7.93 (sbr, 1H); 7.82 (sbr, 2H); 7.78 (s, 1H); 7.66 (dd, 1H); 7.47(dbr, 1H); 7.28 (dd, 1H); 7.20 (dd, 1H); 6.57 (dbr, 1H); 6.10 (dd, 1H).MS (LC-MS): [M + H]⁺ = 613. 5.94

4-fluoro-2-[(2-fluoro- 4-iodophenyl)amino]- 6-(3-{[(2,2,2-trifluoroethyl)- sulfamoyl]amino} phenoxy)benzamide ¹H-NMR: (d6-DMSO,300 MHz) 10.04 (s, 1H); 9.06 (s, 1H); 8.45 (t, 1H); 7.86 (sbr, 1H); 7.83(sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr, 1H); 7.30 (dd, 1H); 7.20 (dd, 1H);6.95 (dbr, 1H); 6.89 (sbr, 1H); 6.75 (dbr, 1H); 6.53 (dbr, 1H; 6.03 (dd,1H); 3.62 (dq, 2H). MS (LC-MS): [M + H]⁺ = 643. 5.95

4-fluoro-2-[(2-fluoro- 4-iodophenyl)amino]- 6-(3-{[(2- methoxyethyl)sulfonyl]amino} phenoxy)benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 9.93 (s,1H); 9.04 (s, 1H); 7.88 (sbr, 1H); 7.85 (sbr, 1H); 7.66 (dd, 1H); 7.48(dbr, 1H); 7.31 (dd, 1H); 7.21 (dd, 1H); 6.98 (dbr, 1H); 6.92 (dd, 1H);6.76 (dd, 1H); 6.57 (dbr, 1H); 6.14 (dd, 1H); 3.62 (t, 2H); 3.36 (t,2H); 3.14 (s, 3H). MS (LC-MS): [M + H]⁺ = 604 5.96

4-fluoro-2-[(2-fluoro- 4-iodophenyl)amino]- 6-{1- (methylsulfonyl)piperazin-2-yl] methoxy}-benzamide MS (LC-MS): [M + H]⁺ = 567 t_(R) =5.67 (HPLC conditions C, hexane/ethanole, 1:1, 0.1% DEA in hexane) 5.97

4-fluoro-2-[(2-fluoro- 4-iodophenyl)amino]- 6-{1- (methylsulfonyl)piperazin-2-yl] methoxy}-benzamide MS (LC-MS): [M + H]⁺ = 567 t_(R) =6.90 (HPLC conditions C, hexane/ethanole, 1:1, 0.1% DEA in hexane) 5.98

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[4-(1H-imidazole-4-sulfonyl)-morpholin- 2-ylmethoxy]- benzamide ¹H-NMR: (d6-DMSO, 300 MHz)12.70 (sbr, 1H); 10.04 (s, 1H); 7.88 (d, 1H); 7.81 (d, 1H); 7.73 (sbr,1H); 7.70 (sbr, 1H); 7.64 (dd, 1H); 7.45 (dbr, 1H); 7.19 (dd, 1H); 6.46(dd, 1H); 6.41 (dbr, 1H); 4.13 (dd, 1H); 4.04 (dd, 1H); 3.89 (dbr, 2H);3.58 (dbr, 1H); 3.53 (dbr, 1H); 3.40 (dbr, 1H); 2.56 (dd, 1H); 2.52-2.38(m, 1H). MS (LC-MS): [M + H]⁺ = 620 5.99

2-({4-[bis(2- methoxyethyl) sulfamoyl]morpholin- 2-yl}methoxy)-4-fluoro-6-[(2-fluoro-4- iodophenyl)amino]- benzamide MS (LC-MS): [M + H]⁺= 685 t_(R) = 5.71 (HPLC conditions C, hexane/ethanole, 6:4) 5.100

2-({4-[bis(2- methoxyethyl) sulfamoyl]morpholin- 2-yl}methoxy)-4-fluoro-6-[(2-fluoro-4- iodophenyl)amino]- benzamide MS (LC-MS): [M + H]⁺= 685 t_(R) = 6.67 (HPLC conditions C, hexane/ethanole, 6:4) 5.101

4-fluoro-2-[(2-fluoro- 4-iodophenyl)amino]- 6-{[4-(morpholin-4-ylsulfonyl)morpholin- 2-yl]methoxy}- benzamide MS (LC-MS): [M + H]⁺ =639 t_(R) = 4.84 (HPLC conditions C, 100% methanole) 5.102

4-fluoro-2-[(2-fluoro- 4-iodophenyl)amino]- 6-{[4-(morpholin-4-ylsulfonyl)morpholin- 2-yl]methoxy}- benzamide MS (LC-MS): [M + H]⁺ =639 t_(R) = 6.67 (HPLC conditions C, 100% methanole) 5.103

2-(1-Acetyl- piperazin-2- ylmethoxy)-4-fluoro- 6-(2-fluoro-4-iodo-phenylamino)- benzamide MS (LC-MS): [M + H]⁺ = 531. 5.104

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(1-methyl- piperazin-2-ylmethoxy)- benzamide MS (LC-MS): [M + H]⁺ = 503 t_(R) = 6.35 (HPLCconditions C, hexane/ethanole, 8:2, 0.1% DEA in hexane) 5.105

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(1-methyl- piperazin-2-ylmethoxy)- benzamide MS (LC-MS): [M + H]⁺ = 503 t_(R) = 8.11 (HPLCconditions C, hexane/ethanole, 8:2, 0.1% DEA in hexane)

Example Compound 6.1 Preparation of2-(3,4-Dihydroxy-4-methyl-pentyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide

In analogy to GP 13, 35 mg of4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(4-methyl-pent-3-enyloxy)-benzamide(0.074 mmol, 1 eq.) were dissolved in Acetone and 0.75 ml of water wereadded to form a suspension. 19 mg N-methyl-morpholino-N-oxide (0.14mmol, 1.9 eq.) were added and the mixture cooled to +3° C. 10 μl of anOsmiumtetroxide solution (2.5 weight % in tert.-butanol) were added andthe mixture stirred for 40 Min in an ice bath and then for 20 h at rt.The reaction mixture was concentrated, 10 ml of water and ethyl acetatewere added and the organic layer was extracted three times with ethylacetate. The organic layer was washed one time with brine, dried oversodium sulfate, filtered off and concentrated to afford 39 mg of crudeproduct which required no further purification.

¹H-NMR: (d6-DMSO, 300 MHz): 10.05 (s, 1H); 7.78 (sbr, 1H); 7.73 (sbr,1H); 7.63 (dd, 1H); 7.45 (ddd, 1H); 7.19 (dd, 1H); 6.45 (dd, 1H); 6.40(dd, 1H); 4.64 (d, 1H); 4.16 (s, 1H); 4.13 (dd, 2H); 3.35-3.25 (m, 1H);2.04 (m, 1H); 1.58 (m, 1H); 1.05 (s, 3H); 1.00 (s, 3H).

MS (ESI): [M+H]⁺=516

The following example compounds 6.2 to 6.11 were prepared in analogy toexample compound 6.1 and GP 13 from the respective olefins.

Example Structure Name Analytical data 6.2

2-(3,4-Dihydroxy-3- methyl-butoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz): 10.12 (s, 1H);7.92 (sbr, 1H); 7.69 (sbr, 1H); 7.63 (dd, 1H); 7.45 (dd, 1H); 7.19 (dd,1H); 6.47 (dd, 1H); 6.39 (dd, 1H); 4.67 (dd, 1H); 4.40 (s, 1H); 4.14(dd, 2H); 3.18 (m, 2H); 1.85 (m, 2H); 1.06 (s, 3H). MS (ESI): [M + H]⁺ =493 6.3

2-(3,4-Dihydroxy-4- methyl-pentyloxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz): 10.05 (s, 1H);7.78 (sbr, 1H); 7.73 (sbr, 1H); 7.63 (dd, 1H); 7.45 (ddd, 1H); 7.19 (dd,1H; 6.45 (dd, 1H); 6.40 (dbr, 1H); 4.64 (d, 1H); 4.16 (s, 1H); 4.13 (dd,2H); 3.35-3.25 (m, 1H); 2.04 (m, 1H); 1.58 (m, 1H); 1.05 (s, 3H); 1.00(s, 3H). MS (ESI): [M + H]⁺ = 516 Optical rotation: −46.9 grd 6.4

2-(3,4-Dihydroxy-4- methyl-pentyloxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz): 10.05 (s, 1H);7.78 (sbr, 1H); 7.73 (sbr, 1H); 7.63 (dd, 1H); 7.45 (ddd, 1H); 7.19 (dd,1H); 6.45 (dd, 1H); 6.40 (dbr, 1H); 4.64 (d, 1H); 4.16 (s, 1H); 4.13(dd,2H); 3.35-3.25 (m, 1H); 2.04 (m, 1H); 1.58 (m, 1H); 1.05 (s, 3H); 1.00(s, 3H). MS (ESI): [M + H]⁺ = 516 Optical rotation: +40.5 grd 6.5

2-(3,4-Dihydroxy-3- methyl-butoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz): 10.12 (s, 1H);7.92 (sbr, 1H); 7.69 (sbr, 1H); 7.63 (dd, 1H); 7.45 (dd, 1H); 7.19 (dd,1H); 6.47 (dd, 1H); 6.39 (dd, 1H); 4.67 (dd, 1H); 4.40 (s, 1H); 4.14(dd, 2H); 3.18 (m, 2H); 1.85 (m, 2H); 1.06 (s, 3H). MS (ESI): [M + H]⁺ =493 Optical rotation: −10.4 grd 6.6

2-(3,4-Dihydroxy-3- methyl-butoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz): 10.12 (s, 1H);7.92 (sbr, 1H); 7.69 (sbr, 1H); 7.63 (dd, 1H); 7.45 (dd, 1H); 7.19 (dd,1H); 6.47 (dd, 1H); 6.39 (dd, 1H); 4.67 (dd, 1H); 4.40 (s, 1H); 4.14(dd, 2H); 3.18 (m, 2H); 1.85 (m, 2H); 1.06 (s, 3H). MS (ESI): [M + H]⁺ =493. Optical rotation: +19.5 grd 6.7

2-(3,4-Dihydroxy-4- methyl-pentyloxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzonitrile MS (ESI): [M + H]⁺ = 489. 6.8

2-(3,4-Dihydroxy-3- methyl-butoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzonitrile MS (ESI): [M + H]⁺ = 475. 6.9

2-[3-(2,3-Dihydroxy- propane-1- sulfonylamino)- phenoxy]-4-fluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide MS (ESI): [M + H]+ = 620. 6.10

6-(3,4-Dihydroxy-4- methyl-pentyloxy)- 3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 400 MHz) 8.62 (s, 1H); 7.79(sbr, 1H); 7.70 (sbr, 1H); 7.52 (dd, 1H); 7.31 (dbr, 1H); 6.97(dd, 1H);6.56 (ddd, 1H); 4.58 (d, 1H); 4.16 (s, 1H); 4.10 (m, 2H); 3.30 (m, 1H);2.00 (m, 1H); 1.54 (m, 1H); 1.04 (s, 3H); 0.99 (s, 3H). MS (LC-MS): [M +H]⁺ = 525. 6.11

2-(3,4-Dihydroxy-4- methyl-pentyloxy)- 3,4,5-trifluoro-6-(2-fluoro-4-iodo- phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 7.73(sbr, 1H); 7.71 (sbr, 1H); 7.65 (d, 1H); 7.47 (dd, 1H); 7.24 (dbr, 1H);6.46 (ddd, 1H); 4.45 (d, 1H); 4.18 (m, 2H); 4.12 (s, 1H); 3.25 (ddd,1H); 1.97 (m, 1H); 1.52 (m, 1H); 1.03 (s, 3H); 0.97 (s, 3H). MS (LC-MS):[M + H]⁺ = 543.

Example Compound 7.0 Preparation of2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-[2-fluoro-4-(4-hydroxy-but-1-ynyl)-phenylamino]-benzamide

In analogy to GP 11b, 47.82 mg of2-((R)-3,4-Dihydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide(0.1 mmol; 1 eq.) were dissolved in 0.5 ml of THF. Then 10.51 mg ofbut-3-yn-1-ol (0.15 mmol; 1.5 eq.) in 0.375 ml of THF was added,followed by 3.51 mg of dichlorobis(triphenylphosphine)palladium (II)(Pd(PPh₃)₂Cl₂) (0.005 mmol; 0.5 eq.) in 417 μl of THF and 130.73 mg of a1M solution of tetra-N-butylammonium fluoride in THF (0.5 mmol; 5 eq.).The mixture was then allowed to react for 40 min at 110° C. in amicrowave oven (600W; max. 6 bar). The crude reaction mixture wasdirectly submitted to preparative HPLC to yield 31.4 mg (74.69% yield;0.075 mmol) of the pure target compound.

t_(R)=0.93 (HPLC conditions A); MW_(calc)=420.4; MW_(found)=421

The following Example compounds 7.1 to 7.3 were prepared in analogy tothe example above by Sonogashira couping of the respective iodidesubstrates with TMS-acetylene or phenyl acetylene optionally followed byTMS deprotection.

Example Structure Name Analytical data 7.1

2-((R)-3,4-Dihydroxy- 4-methyl-pentyloxy)- 6-(4-ethynyl-2-fluoro-phenylamino)-4- fluoro-benzamide ¹H-NMR: (d6-DMSO, 300 MHz): 10.14 (s,1H); 7.78 (sbr, 1H); 7.77 (sbr, 1H); 7.41-7.33 (m, 2H); 7.22 (dd, 1H);6.56-6.47 (m, 2H); 4.63 (d, 1H); 4.18-4.10 (m, 2H); 4.16 (s, 1H); 4.14(s, 1H); 3.35-3.25 (m, 1H); 2.04 (m, 1H); 1.58 (m, 1H); 1.05 (s, 3H)1.00 (s, 3H). MS (ESI): [M + H]⁺ = 405 7.2

2-[3-[[(dimethylamino) sulfonyl]amino] phenoxy]-4-fluoro-6-[(4-ethynyl-2- fluorophenyl)amino]- benzamide ¹H-NMR (d₆-DMSO; 300 MHz):10.02 (s, 1H); 9.16 (s, 1H); 7.89 (sbr, 1H); 7.86 (sbr, 1H); 7.42-7.35(m, 2H); 7.32-7.21 (m, 2H); 6.95 (dd, 1H); 6.90 (dd, 1H); 6.75-6.67 (m,2H); 6.17 (dd, 1H); 4.17 (s, 1H); 2.66 (s, 6H). MS (ESI): [M + H]⁺ = 4877.3

2-[3- [[(propylamino) sulfonyl]amino] phenoxy]-4-fluoro-6-[(4-ethynyl-2- fluorophenyl)amino]- benzamide ¹H-NMR (d₆-DMSO; 400 MHz):9.81 (s, 1H); 9.22 (s, 1H); 7.89 (sbr, 1H); 7.84 (sbr, 1H); 7.42-7.35(m, 2H); 7.28 (dd, 1H); 7.24 (dd, 1H); 6.96 (dd, 1H); 6.91 (dd, 1H);6.72 (dd, 1H); 6.67 (dd, 1H); 6.06 (dd, 1H); 4.17 (s, 1H); 2.74 (q, 2H);1.33 (dt, 2H); 0.71 (t, 3H). MS (ESI): [M + H]⁺ = 501. 7.4

2-{3- [(dimethylsulfamoyl) amino]phenoxy}-6- [(4-ethynyl-2-fluorophenyl)amino]- 3,4,5- trifluorobenzamide MS (LC-MS): [M + H]⁺ =523.

Example Compound 8.1 Preparation of methanesulfonic acid(R)-4-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-2-hydroxy-butylester

In analogy to GP 14, 1.1 g of2-((R)-3,4-dihydroxy-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide(2.3 mmol, 1 eq.) were dissolved in 23 mL NMP and treated with 0.2 mLmethansulfonyl chloride (2.53 mmol, 1.1 eq.) and 3.04 mL collidine (23mmol, 10 eq.) at 0° C. and kept at this temperature overnight.Preparative HPLC purification of the crude reaction mixture provided thetarget compound.

MS (ESI): [M+H]⁺=557.

Example Compound 8.2 Preparation of4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[(R)-3-hydroxy-4-(2-hydroxy-ethylamino)-butoxy]-benzamide

In analogy to GP 15, 1 eq. of methanesulfonic acid(R)-4-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-2-hydroxy-butylester was dissolved in DMF (6 mL per 300 mg mesylate) and treated with20 eq. hydroxyethylamine and stirred until final reaction turnover (byLCMS). Preparative HPLC purification provided the analytically puretarget compound.

t_(R)=1.07 (HPLC conditions A); MW_(calc)=521.3; MW_(found)=522

The following Example compounds 8.3 and 8.4 were prepared in analogy toExample compound 8.2 by applying other commercially available amine tothe described reaction conditions.

Example Structure Name Analytical data 8.3

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-{(R)-3-hydroxy-4-[(2-methoxy-ethyl)- methyl-amino]- butoxy}-benzamide t_(R) = 1.11 (HPLCconditions A); MW_(calc) = 549.3; MW_(found) = 550 8.4

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-[(R)-3-hydroxy-4-(2-methoxy- ethylamino)-butoxy]- benzamide t_(R) = 1.11 (HPLC conditionsA); MW_(calc) = 535.3; MW_(found) = 536

The following Example compound 9.1 was synthesized by applying the aforedescribed procedures starting from the respective2,6-difluorobenzonitriles by stepwise substitution of the 6- and2-fluoro substituent, subsequent nitrite hydrolysis and finallyacetonide cleavage.

Example Structure Name Analytical data 9.1

2-((R)-3,4-Dihydroxy- butoxy)-6-(2-fluoro- 4-iodo-phenylamino)-4-methoxy- benzamide ¹H-NMR: (d6-DMSO, 300 MHz) 10.59 (s, 1H); 7.81 (br.s, 1H); 7.65 (dd, 1H); 7.56 (br. s, 1H); 7.47 (d, 1H); 7.29 (t, 1H);6.17 (d, 1H); 6.30 (d, 1H); 4.76 (d, 1H); 4.62 (t, 1H); 4.15-4.25 (m,2H); 3.74 (s, 3H); 3.60-3.68 (m, 1H); 3.25-3.41 (m, 2H); 1.94-2.06 (m,1H); 1.65-1.77 (m, 1H).

The following Example compounds 10.1 to 10.8 were synthesized bystandard transformations from the afore described example compounds,including i) Amide formation, ii) Suzuki coupling, epoxidation andsubsequent nucleophilic epoxide opening, iv) alkylation, v) acetonidecleavage, vi) ester formation, vii) oxidative diol cleavage, and viii)protecting group cleavage.

Example Structure Name Analytical data 10.1

2-((R)-3,4-Dihydroxy- butoxy)-4-fluoro-6- (3-fluoro-biphenyl-4-ylamino)-benzamide t_(R) = 1.28 (HPLC conditions A); MW_(calc) = 428.4;MW_(found) = 429 10.2

2-((R)-4-Chloro-3- hydroxy-butoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide ¹H-NMR: (d6-DMSO, 600 MHz) 9.86 (s, 1H);7.76-7.79 (m, 2H); 7.67 (dd, 1H); 7.49 (d, 1H); 7.22 (t, 1H); 6.51 (dd,1H); 6.44 (dd, 1H); 5.33 (d, 1H); 4.12-4.19 (m, 2H); 3.86-3.90 (m, 1H);3.61 (m, 2H); 2.01-2.07 (m, 1H); 1.79-1.84 (m, 1H). MS (ESI): [M + H]⁺ =497/499 (Cl isotope pattern). 10.3

N-Benzyl-2-((R)-3,4- dihydroxy-butoxy)-4- fluoro-6-(2-fluoro-4-iodo-phenylamino)- benzamide MS (ESI): [M + H]⁺ = 569. 10.4

Phthalic acid mono- {(R)-4-[2-cyano-5- fluoro-3-(2-fluoro-4-iodo-phenylamino)- phenoxy]-2-hydroxy- butyl} ester MS (ESI): [M + H]⁺ =609. 10.5

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3-oxo-butoxy)-benzonitrile MS (ESI): [M + H]⁺ = 443. 10.6

6-[3-[[(dimethylamino) sulfonyl](methyl)- amino]phenoxy]-4-fluoro-2-[(2-fluoro-4- iodophenyl)amino]- benzamide ¹H-NMR (d₆-DMSO; 300MHz): 9.02 (s, 1H); 7.86 (sbr, 2H); 7.66 (dd, 1H); 7.47 (dd, 1H); 7.41(dd, 1H); 7.27-7.17 (m, 3H); 6.99 (dd, 1H); 6.54 (dd, 1H); 6.04 (dd,1H); 3.19 (s, 3H); 2.70 (S, 6H). MS (ESI): [M + H]⁺ = 603 10.7

3-[2-Carbamoyl-5- fluoro-3-(2-fluoro-4- iodo-phenylamino)-phenoxy]-benzoic acid ¹H-NMR (d₆-DMSO; 300 MHz): 13.15 (s, 1H); 8.98 (s,1H); 7.92 (sbr, 1H); 7.83 (sbr, 1H); 7.72 (dbr, 1H); 7.66 (dd, 1H); 7.59(sbr, 1H); 7.51 (dd, 1H); 7.47 (dbr, 1H); 7.33 (ddd, 1H); 7.22 (dd, 1H);6.58 (dd, 1H); 6.17 (dd, 1H). MS (ESI): [M + H]⁺ = 511 10.8

4-Fluoro-2-(2-fluoro- 4-iodo-phenylamino)- 6-(3- methanesulfonyl-phenoxy)-benzamide ¹H-NMR (d₆-DMSO; 400 MHz): 8.87 (s, 1H); 7.94 (sbr,1H); 7.84 (sbr, 1H); 7.71 (ddd, 1H); 7.69-7.63 (m, 3H); 7.48 (dd, 1H);7.40 (ddd, 1H); 7.21 (dd, 1H); 6.59 (ddd, 1H); 6.25 (dd, 1H); 3.22 (s,3H). MS (ESI): [M + H]⁺ 545=

Example Compound 11.1 Preparation of2-[3-(3,3-Dimethyl-ureido)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide

In analogy to GP 10, 45 mg of{2-Carbamoyl-3-[3-(3,3-dimethyl-ureido)-phenoxy]-5-fluoro-phenyl}-(2-fluoro-4-iodo-phenyl)-carbamicacid tert-butyl ester (0.071 mmol; 1 eq.) were dissolved in 2 ml DCM and0.11 ml TFA (1.42 mmol; 20 eq.) were added. The mixture was stirred atRT for 12 h and then concentrated. The residue was partitioned between10 ml of ethyl methyl ketone and 5 ml of 1M aq. sodium hydroxidesolution. The aqueouse layer was extracted twice with ethyl methylketone (10 ml each). The combined organic layers were washed with 10 mlhalf concentrated brine, dried via silicone filter and concentrated toafford 56.4 mg of the crude product. Purification was achieved by flashchromatography to afford 6.39 mg (16.31% yield; 0.012 mmol).

¹H-NMR: (d6-DMSO, 300 MHz) 9.17 (s, 1H); 8.37 (s, 1H); 7.84 (sbr, 1H);7.81 (sbr, 1H); 7.66 (dd, 1H); 7.47 (dbr, 1H); 7.30-7.18 (m, 4H); 6.65(dbr, 1H); 6.54 (dbr, 1H); 6.07 (dd, 1H); 2.87 (s, 6H).

MS (ESI): [M+H]⁺=553

Biological Evaluation

The utility of the compounds of the present invention can beillustrated, for example, by their activity in vitro in the in vitrotumor cell proliferation assay described below. The link betweenactivity in tumor cell proliferation assays in vitro and anti-tumoractivity in the clinical setting has been very well established in theart. For example, the therapeutic utility of taxol (Silvestrini et al.Stem Cells 1993, 11(6), 528-35), taxotere (Bissery et al. Anti CancerDrugs 1995, 6(3), 339), and topoisomerase inhibitors (Edelman et al.Cancer Chemother. Pharmacol. 1996, 37(5), 385-93) were demonstrated withthe use of in vitro tumor proliferation assays.

Demonstration of the activity of the compounds of the present inventionmay be accomplished through in vitro, ex vivo, and in vivo assays thatare well known in the art. For example, to demonstrate the activity ofthe compounds of the present invention, the following assays may beused.

Biological Assays Assay 1 MEK Biochemical Assay: DELFIA

The DELFIA MEK kinase assay was used to monitor the activity of MEKinhibitors. The kinase reaction was carried out in a 96-wellmicrotitration plate by firstly mixing 70 μL of kinase reaction buffer(50 mM HEPES pH 7.5, 5 mM NaF, 5 mM glycerophosphate, 1 mM sodiumvanadate, 10 mM MgCl₂, 1 mM DTT and 1% (v/v) DMSO) with 20 nM GST-MEK,20 nM His-Raf and 100 nM biotinylated ERK1 (final concentration). Thencompounds with final concentrations of 1 μM, 0.3 μM, 0.1 μM, 0.03 μM,0.01 μM, 0.003 μM, 0.001 μM, 0.0003 μM and 0 μM were added to generatethe dose response inhibition curve. The kinase reaction was started byadding 20 μL of ATP (final concentration 100 μM). After 2 h incubation,the reaction was terminated by adding 20 μl of 0.5 M EDTA. Then 100 μLof the reaction mixture was transferred to a 96 well Streptavidin plate(cat #15120, Pierce Inc. Rockford, Ill.) and subsequently incubated for2 h. After collecting the biotinylated substrate ERK1, the plate waswashed with TBST. An antibody against phospho-p44/42 MAPK (cat# 91065,Cell Signaling Technologies, Danvers, Mass.) was added and bond to thephosphorylated substrate. Thereafter, incubation with anEuropium-labeled anti-mouse antibody (cat# AD0124, Wallac Inc, Turku,Finland) followed by a washing step was carried out. The EnhancementSolution was added to dissociate europium ions into solution, where theyformed highly fluorescent chelates with the components of theenhancement solution. The fluorescence of each sample was proportionalto kinase activity and counted on a VICTOR5 instrument (Wallac Inc.).Data analysis was performed using Analyze5 software for IC₅₀ analysis.

Assay 2 MEK1 Activation Kinase Assay

The kinase Cot1 activates MEK1 by phosphorylating its activation loop.The inhibitory activity of compounds of the present invention on thisactivation of MEK1 was quantified employing the HTRF assay described inthe following paragraphs.

N-terminally His6-tagged recombinant kinase domain of the human Cot1(amino acids 30-397, purchased from Millipore, cat. no 14-703) expressedin insect cells (SF21) and purified by Ni-NTA affinity chromatographywas used as kinase. As substrate for the kinase reaction the unactiveC-terminally His6-tagged GST-MEK1 fusion protein (Millipore cat. no14-420) was used.

For the assay 50 nl of a 100 fold concentrated solution of the testcompound in DMSO was pipetted into a black low volume 384 wellmicrotiter plate (Greiner Bio-One, Frickenhausen, Germany), 3 μl of asolution of 24 nM GST-MEK1 and 166.7 μM adenosine-tri-phosphate (ATP) inassay buffer [50 mM Tris/HCl pH 7.5, 10 mM MgCl₂, 2 mM dithiothreitol,0.01% (v/v) Igepal CA 630 (Sigma), 5 mM β-phospho-glycerol] were addedand the mixture was incubated for 10 min at 22° C. to allow pre-bindingof the test compounds to the GST-MEK1 before the start of the kinasereaction. Then the kinase reaction was started by the addition of 2 μlof a solution of Cot1 in assay buffer and the resulting mixture wasincubated for a reaction time of 20 min at 22° C. The concentration ofCot1 in the assay was adjusted depending of the activity of the enzymelot and was chosen appropriate to have the assay in the linear range,typical enzyme concentrations were in the range of about 2 ng/μl (finalconc. in the 5 μl assay volume). The reaction was stopped by theaddition of 5 μl of a solution of HTRF detection reagents (13 nM antiGST-XL665 [# 61GSTXLB, Fa. Cis Biointernational, Marcoule, France], 1 nMEu-cryptate labelled anti-phospho-MEK 1/2 (Ser217/221) [#61P17KAZ, Fa.Cis Biointernational],) in an aqueous EDTA-solution (100 mM EDTA, 500 mMKF, 0.2% (w/v) bovine serum albumin in 100 mM HEPES/NaOH pH 7.5).

The resulting mixture was incubated 2 h at 22° C. to allow the bindingof the phosphorylated GST-MEK1 to the anti-GST-XL665 and the Eu-cryptatelabelled anti-phospho-MEK 1/2 antibody. Subsequently the amount ofSer217/Ser221-phosphorylated substrate was evaluated by measurement ofthe resonance energy transfer from the Eu-Cryptate-labelledanti-phospho-MEK antibody to the anti-GST-XL665. Therefore, thefluorescence emissions at 620 nm and 665 nm after excitation at 350 nmwas measured in a HTRF reader, e.g. a Rubystar (BMG Labtechnologies,Offenburg, Germany) or a Viewlux (Perkin-Elmer). The ratio of theemissions at 665 nm and at 622 nm was taken as the measure for theamount of phosphorylated substrate. The data were normalised (enzymereaction without inhibitor=0% inhibition, all other assay components butno enzyme=100% inhibition). Normally test compound were tested on thesame microtiter plate at 10 different concentrations in the range of 20μM to 1 nM (20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μM, 82 nM, 27 nM, 9.2nM, 3.1 nM and 1 nM, dilution series prepared before the assay at thelevel of the 100 fold conc. stock solutions by serial 1:3 dilutions) induplicate values for each concentration and IC₅₀ values were calculatedby a 4 parameter fit using an inhouse software.

The following representative example compounds show an IC50 below 1 μMin this assay:

2.1; 2.16; 2.17; 2.18; 2.19; 2.20; 4.5; 4.9; 4.17 to 4.23; 4.25; 4.27;4.33; 4.34; 4.37; 5.2; 5.3; 5.7; 5.24; 5.30 to 5.34; 5.36 to 5.39; 5.41;5.48; 5.49; 5.66 to 5.69; 5.75 to 5.84; 5.93 to 5.95; 6.1 to 6.6; 7.2 to7.4; 10.6; 10.7; 10.8

The following representative Example compounds show an IC50 as follows:

Assay 2 IC50 values (nanomolar) Example (MEK1 activation kinase assay)number (values are mean values from 2 or more measurements) 2.1 21.82.16 47.3 2.17 39.8 2.18 9.91 2.19 152 2.20 16.5 4.9 93.6 4.17 61.3 4.1869.9 4.19 80.1 4.20 89.3 4.21 248 4.22 163 4.23 132 4.25 182 4.27 2584.33 31.5 4.34 23.5 4.37 26.6 5.2 24.0 5.3 28.1 5.7 18.5 5.24 25.9 5.30138 5.31 153 5.32 35.4 5.33 91.6 5.34 96.5 5.36 14.5 5.37 20.4 5.38 55.35.39 438 5.41 22.2 5.48 16.9 5.49 15.7 5.66 36.5 5.67 63.4 5.68 43.25.69 18.3 5.75 103 5.76 70.3 5.77 127 5.78 86.2 5.79 77.8 5.80 137 5.8196.4 5.82 49.9 5.83 143 5.84 75.4 5.93 86.0 5.94 55.5 5.95 25.1 6.1 19.76.2 69.3 6.3 30.6 6.4 29.5 6.5 172 6.6 80.3 7.2 13.5 7.3 46.7 7.4 12.310.6 49.1 10.7 33.2 10.8 29.4

Assay 3 Phospho-ERK Mechanistic Assay

A375 and Colo205 cells were plated in RPMI 1640 growth mediumsupplemented with 10% FBS at 25,000 cells per well in 96-well tissueculture plates. Cells were incubated overnight in a humidified incubatorcontaining 5% CO₂ at 37° C. The following day, to prepare the assayplates, anti-rabbit Meso-Scale Discovery (MSD) plates (cat# L41RA-1,Meso-Scale Discovery, Gaithersburg, Md.) were blocked with 100 μl of 5%MSD blocking buffer for 1 h at room temperature, after which they werewashed three times with 200 μl of TBST buffer. The phospho-ERK rabbitpolyclonal antibody (cat# 9101, Cell Signaling Technologies, Danvers,Mass.) diluted at 1:200 into 2.5% of MSD Blocker A-TBST was added (25μl) to each well and the plate was then incubated 1 h at roomtemperature with shaking. The plates were then washed once withphosphate buffered saline (PBS) and ready to receive the cell lysates.While the preparation of the assay plates was ongoing, test compoundswere added to the wells of cell-containing plates from the previous day,serially diluted in RPMI 1640 medium containing 10% FBS, 0.1% bovineserum albumin (BSA) and 0.03% DMSO and the plates were incubated for 1.5h at 37° C. After this incubation, the compound-treated plates werewashed three times with PBS, lysed in 30 μl of Bio-Rad lysis buffer (cat#98601, Bio-Rad Laboratories, Hercules, Calif.) and then left shaking onice for 30 min. The lysates were then loaded on the phospho-ERK coatedMSD plates and the plates Incubated overnight at 4° C. The followingday, the plates were washed three times with TBST and 25 μl of 1:3000diluted total ERK monoclonal antibody (Cat# 610123, BD Biosciences, SanDiego, Calif.) was added to the plates that were then incubated 1 h atroom temperature with shaking. After the incubation the plates werewashed three times with TBST as described earlier and 25 μl of MSDsulfo-tag anti-mouse antibody (cat #R32AC-5) diluted 1:1000 were addedinto each well. The plates were Incubated 1 h at room temperature withshaking, then washed four times with TBST. Just prior to reading theplates, 150 μl of MSD Read buffer T was added and the plates were readimmediately on the MSD instrument. Data analysis was performed usingAnalyze5 software for IC₅₀ analysis.

Assay 4

Alternative Conditions for Mechanistic pERK Assay

For the measurement of ERK1/2 phosphorylation in tumor cell lines asingleplex Mesoscale Discovery (MSD) assay is used. This assay is builtup like a sandwich immunoassay. Cell lysates generated from differenttumor cell lines treated with serially diluted MEK inhibitor compoundswere loaded on the MSD plates. Phosphorylated ERK1/2 present in thesamples binds to the capture antibody immobilized on the workingelectrode surface. The sandwich is completed by binding of a detectionantibody to the immobilzed phospho-ERK1/2. This detection antibody islabeled with an electro-chemiluminescent compound. Applying voltage tothe plate electrodes causes the labels, bound to the electrode surfacevia the antibody-phospho ERK1/2 sandwich complex, to emit light. Themeasurement of the emitted light allows a quantitative determination ofthe amount of phosphorylated ERK1/2 present in the sample. In detail, alinear range for the measurement of phosphoERK signals must bedetermined for every cell line used in the assay by titrating differentcell numbers. For the final assay, the previously determined cell numberis seeded in 96 well plates. 24 h after seeding, cells were treated for1.5 h with serially diluted allosteric MEK inhibitor compounds beforethe cells were lysed and lysates were transferred in the MSD assayplate. The manufacturer's protocol was changed in that the binding stepof the phosphorylated ERK to the capture antibody was performed overnight at 4° C. instead of 3 h at room temperature, leading to a bettersignal strength.

A375 or Colo205 cells were plated in 50 μL DMEM growth medium (BiochromFG 0435) supplemented with 10% FBS (Biochrom #S0410) (A375),respectively in RPMI growth medium (Biochrom FG1215) supplemented with10% FBS (Biochrom #S0410), 10 mM HEPES (Biochrom L1613), 4.5 g/L Glucoseand 1 mM sodiumpyruvat (Biochrom L0473) (Colo-205) at 45000 cells perwell in 96-well tissue culture plates. Cells were incubated overnight ina humidified incubator containing 5% CO₂ at 37° C.

The Phospho-ERK by Mesoscale Discovery (MSD) (# K111DWD) assay wasperformed according to the manufacturer's recommendations. In brief theprotocol was:

The day after cell seeding, to prepare the assay plates, MSD wereblocked with 150 μl of MSD blocking buffer for 1 h at room temperature,after which they were washed is four times with 150 μl of Tris Washbuffer. While the preparation of the assay plates was ongoing, testcompounds were added to the wells of cell-containing plates from theprevious day, serially diluted in respective growth medium containing10% FBS and 0.1% DMSO and the plates were incubated for 1.5-2 h at 37°C. After this incubation the medium was aspirated, cells were lysed in50 μl lysis buffer and then left shaking for 30 min at 4° C. 25 μL ofthe lysates were then loaded on the blocked MSD plates and the platesIncubated overnight at 4° C. The following day, the plates were washedfour times with Tris wash buffer and 25 μl detection antibody solutionwas added to the plates that were then incubated 1 h at room temperaturewith shaking. After the incubation the plates were washed four timeswith Tris wash buffer 150 μl of MSD Read buffer T was added and theplates were read immediately on the MSD instrument. Data analysis wasperformed using an in-house software for IC50 analysis.

Assay 5 In Vitro Tumor Cell Proliferation Assay:

The adherent tumor cell proliferation assay used to test the compoundsof the present invention involves a readout called Cell Titre-Glodeveloped by Promega (Cunningham, B A “A Growing Issue: CellProliferation Assays. Modern kits ease quantification of cell growth”The Scientist 2001, 15(13), 26, and Crouch, S P et al., “The use of ATPbioluminescence as a measure of cell proliferation and cytotoxicity”Journal of Immunological Methods 1993, 160, 81-88).

A375 and Colo205 cells were plated in RPMI 1640 growth mediumsupplemented with 10% FBS at 3,000 cells per well in 96-well tissueculture plates. Cells were incubated overnight in a humidified incubatorcontaining 5% CO₂ at 37° C. The following day, test compounds were addedto wells, serially diluted in RPMI 1640 medium containing 10% FBS and0.03% DMSO and the plates were incubated for 72 h at 37° C. Evaluationof cell density was made at different time points (0 and 72 hpost-dosing) by adding to each well 150 μl of Cell Titer Glo reagent(cat# G7572, Promega, Madison Wis.) followed by incubation of the plateson a rotator for 10 min at room temperature and then reading of theluminescence on a Victor3 instrument. Data analysis was performed usingAnalyze5 software for IC₅₀ analysis.

Assay 6 In Vitro Tumor Cell Proliferation Assay in A375 Cells (CellTiter Glow [CTG] Assay)

A375 cells [human malignant melanoma cells, ATCC # CRL-1619, expressingmutant BRAF V600E] were plated at a density of 3000 cells/well in 96well black-clear bottom tissue culture plates (Costar 3603 black/clearbottom) in 100 μL/well DMEM medium (Biochrom; FG0435; +3,7 g/L odiumbicarbonate; +4.5 g/L D-Glucose) with 10% Fetal Bovine Serum (FBS) andstable Glutaminincubated at 37° C. Plate sister wells in separate platefor time zero determination. Incubate all plates overnight 37° C. Takedown time zero plate: add 67 μL/well CTG solution (Promega Cell TiterGlo solution) to time zero wells in sister plate; the plates were mixedfor 2 min on orbital shaker to ensure cell lysis, incubate 10 minutes,read luminescence on VICTOR3 (Perkin Elmer). Twenty-four hours aftercell seeding, test compounds diluted in 50 μL medium are added at afinal concentration range from as high 10 μM to as low 300 pM dependingon the activities of the tested compounds in serial dilutions at a finalDMSO concentration of 0.4%. Cells were incubated for 72 hours at 37° C.after addition of the test compound. Then, using a Promega Cell TiterGlo Luminescent® assay kit, 100 microliters lysis buffer containing ofthe enzyme luciferase and its substrate, luciferin mixture, were addedto each well and incubated for 10 min at room temperature in the dark tostabilize luminescence signal. The samples were read on VICTOR3 (PerkinElmer) using Luminescence protocol. The percentage change in cell growthwas calculated by normalizing the measurements to the extinctions of thezero point plate (=0%) and the extinction of the untreated (0 μM) cells(=100%). The IC50 values were determined by means of a 4-parameter fitusing the company's own software.

Alternatively, the cell proliferation was measured by crystal violet(CV) staining:

Assay 7

Cultivated human A375 cells were plated out in a density of 1500cells/measurement point in 200 μl of growth medium (DMEM/HAMS F12(Biochrom; FG4815) with 10% FBS and 2 mM Glutamine) in a 96-wellmultititer plate. After 24 hours, the cells from a plate (zero plate)were stained with crystal violet (see below), while the medium in theother plates was replaced by fresh culture medium (200 μl) to which thetest substances had been added in various concentrations (0 μM, and inthe range 0.3 nM-30 μM; the final concentration of the solvent dimethylsulphoxide was 0.5%). The cells were incubated in the presence of thetest substances for 4 days. The cell proliferation was determined bystaining the cells with crystal violet: the cells were fixed by adding20 μl/measurement point of an 11% glutaraldehyde solution at roomtemperature for 15 min. After the fixed cells had been washed threetimes with water, the plates were dried at room temperature. The cellswere stained by adding 100 μl/measurement point of a 0.1% crystal violetsolution (pH adjusted to pH 3 by adding acetic acid). After the stainedcells had been washed three times with water, the plates were dried atroom temperature. The dye was dissolved by adding 100 μl/measurementpoint of a 10% acetic acid solution, and the extinction was determinedby photometry at a wavelength of 595 nm. The percentage change in cellgrowth was calculated by normalizing the measurements to the extinctionsof the zero point plate (=0%) and the extinction of the untreated (0 μM)cells (=100%). The IC50 values were determined by means of a 4-parameterfit using the company's own software.

In vitro inhibition of proliferation of further cancer cell lines can bemeasured in analogy to the afore-described procedures. Details forexemplary further tumor cells lines are given below:

cell Indication Ras or number (all Raf per Cells human) Mutation Methodwell Medium A-431 epidermoid CTG 3000 DMEM/HAMS F12 cancer (Biochrom;FG4815) + 10% FBS and stable Glutamin A-431 epidermoid CTG 3000DMEM/HAMS F12 non- cancer (Biochrom; FG4815) + 10% adherent FBS andstable Glutamin (Plates were coated with poly-2-hydroxy-ethylmethacrylate before cell seeding) A549 lung KRAS CTG 2000 DMEM/HAMSF12 carcinoma G12S (Biochrom; FG4815) + 10% FBS and stable GlutaminColo-205 colon BRAF CTG 3000 RPMI1640 (Biochrom; carcinoma V600EFG1215) + 10% heat inactivated FBS and stable glutamin + 1x non-essentiell amino acid + 1 mM Sodiumpyruvat + 10 mM Hepes HCT-116 colonKRAS CTG 3000 DMEM/HAMS F12 cancer, G13D (Biochrom; FG4815) + 10% FBSand stable Glutamin HT-29 colon BRAF CTG 2000 DMEM/HAMS F12 cancer V600E(Biochrom; FG4815) + 10% FBS and stable Glutamin Lox melanoma BRAF CTG2000 RPMI1640 (Biochrom; V600E FG1215) + 10% heat inactivated FBS andstable glutamin + 1x non- essentiell amino acid + 1 mM SodiumpyruvatMCF-7 breast CTG 5000 RPMI1640 (F1275; w/o cancer phenol red) + 10%FBS + 2 mM Glutamin + 2 mU/mL Insulin + 1E-10M estradiol

Assay 8 In Vivo Efficacy Studies: Staged Human Xenograft Models

The in vivo anti-tumor activity of lead compounds was assessed in miceusing xenograft models of human BRAF mutant melanoma and coloncarcinomas. The Female athymic NCR nude mice were implantedsubcutaneously with either a human melanoma (LOX), or a human colon(Colo205) carcinoma lines acquired from American Type Culture Collection(ATCC, Maryland). Treatment was initiated when tumors reachedapproximately 100 mg in size. Compounds were administered orally andfreshly prepared in PEG/water (80%/20% respectively). The general healthof mice was monitored and mortality was recorded daily. Tumor dimensionsand body weights were recorded twice a week starting with the first dayof treatment. Animals were euthanized according to Bayer IACUCguidelines. Treatments producing greater than 20% lethality and/or 20%net body weight loss were considered ‘toxic’.

Tumor growth was measured with electronic calipers three times a weekand tumor weight (mg) calculated according to the following formula:[length (mm)×width (mm)²]/2. Anti-tumor efficacy was determined as afunction of tumor growth inhibition (% TGI). TGI is calculated on daysof measurement using the following formula: (100−mean tumor value oftreated (T)/mean tumor of control value (C)×100)=% T/C. The control usedin the calculations is either the “untreated control” or “vehicle”,whichever provides the most conservative representation of the data. Acompound demonstrating a TGI of greater than or equal to 50% isconsidered active. Statistical significance is determined using either aone-tailed or two-tailed Student's T-Test. The compounds that weretested showed significant dose-dependent tumor growth inhibition in bothLOX and Colo205 models.

Compounds of the invention were tested for activity using one or more ofthe assay procedures presented above.

It is believed that one skilled in the art, using the precedinginformation and information available in the art, can utilize thepresent invention to its fullest extent. Those skilled in the art willrecognize that the invention may be practiced with variations on thedisclosed structures, materials, compositions and methods withoutdeparting from the spirit or scope of the invention as it is set forthherein and such variations are regarded as within the ambit of theinvention. The compounds described in the examples are intended to berepresentative of the invention, and it will be understood that thescope of the invention is not limited by the scope of the examples. Thetopic headings set forth above are meant as guidance where certaininformation can be found in the application, but are not intended to bethe only source in the application where information on such topics canbe found. All publications and patents cited above are incorporatedherein by reference.

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1. A compound of general formula (I):

in which: R¹ and R² are the same or different and are independently ahydrogen atom, a halogen atom, a C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, or —CN group, in which at least one of R¹ and R² is ahalogen atom; R³ is, in each occurrence, independently, a halogen atom,a C₁-C₄-alkyl or —CN group; q is an integer of 0, 1, 2, or 3; R⁴ is ahydrogen atom or a C₁-C₆-alkyl group; R⁵ is a —C(═O)R⁷, —C(═O)OR⁷,—C(═O)N(R⁷)(R⁸), —NHC(═O)R⁷, —S(═O)₂R⁷, —NHS(═O)₂R⁷, —S(═O)₂NR⁷R⁸, —NO₂,—CN, or a

in which: each of Z¹, Z², Z³ and Z⁴ is independently —CH—,—C(C₁-C₆-alkyl)-, —C(═O)—, —S—, —O—, —N— or —NH, such that at least oneof Z¹, Z², Z³ and Z⁴ is —N— or —NH—; X is —O—, —NH—, —N(C₁-C₆-alkyl)-,—S—, —S(═O)₂—, —C(═O)—, —C(═O)O—, or —C(═O)NH—; R⁶ is —(CR¹⁵₂)_(n)—(CR¹⁵(OR¹¹))—(CR¹⁵ ₂)_(m)—R⁹, or —(CH₂)_(n)—Y; Y is: a) an aryl,heteroaryl, cycloalkyl or heterocycloalkyl group, said aryl, heteroaryl,cycloalkyl or heterocycloalkyl group being substituted with one or more—(CH₂)_(o)Y′ groups, in each occurrence of said —(CH₂)_(o)Y′ group: o isan integer of 0; and Y′ is, independently: a C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkoxyalkyl, cycloalkyl, or heterocycloalkylgroup, or an —OR^(c′) group, in each occurrence of which, R^(c′) is,independently:  a —C(═O)R^(e) group, in which R^(e) is defined infra, or an —S(═O)₂R^(e) group, in which R^(e) is defined infra, or  aC₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroarylgroup, in which C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl group, are, independently of each other, optionallysubstituted one or more times with:  a halogen atom, or  an —OH, or  anaryl group, or  an —OR^(f) group, in which R^(f) is as defined infra, or an —NR^(d1)R^(d2) group, in which R^(d1) and R^(d2) are as definedinfra, or  a —OP(═O)(OR^(f))₂ group, in which R^(f) is as defined infra;or an —NR^(d1)R^(d2) group, as defined infra, with the provisos that: when one of R^(d1) and R^(d2) is H, then the other of R^(d1) and R^(d2)is neither H nor C₁-C₆-alkyl, and  R^(d1) and R^(d2) cannotsimultaneously be C₁-C₆-alkyl; or an —NR^(a)S(═O)₂R^(b) group, asdefined infra, with the proviso that:  when R_(a) is H, then R_(b) isnot C₁-C₆-alkyl; Or an —S(═O)₂R^(b) group, in which R^(b) is as definedinfra, with the provisos that when R^(b) is —NR^(d1)R^(d2):  R^(d1) andR^(d2) are not both H,  when R^(d1) is H, then R^(d2) is notC₁-C₆-alkyl,  R^(d1) and R^(d2) are not both C₁-C₆-alkyl, or a—C(═O)R^(b) group, in which R^(b) is as defined infra; or b) an aryl,heteroaryl, cycloalkyl or heterocycloalkyl group, said aryl, heteroaryl,cycloalkyl or heterocycloalkyl group being substituted with one or more—(CH₂)_(o)R¹⁴ groups, in each occurrence of said —(CH₂)_(o)R¹⁴ group: ois an integer of 1 or 2; and R¹⁴ is as defined infra; or c) aC₂-C₁₀-alkenyl or C₅-C₁₀-cycloalkenyl group, said C₂-C₁₀-alkenyl orC₅-C₁₀-cycloalkenyl group being optionally substituted with one or more—(CH₂)_(o)R¹⁴ groups, in which o and R¹⁴ are as defined infra; R⁷ and R⁸are independently a hydrogen atom, a —N(R¹²)(R¹³), —OH, —C₁-C₆-alkoxy,—C₁-C₆-alkyl, —CF₃, —O—(CH₂)_(n)—(CH(OR¹¹))—(CH₂)_(m)—R⁹,—O—(CH₂)_(n)-cycloalkyl, aryl, heteroaryl, cycloalkyl orheterocycloalkyl group, in which aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are, independently of each other, optionallysubstituted with one or more halogen atoms, C₁-C₆-alkyl or C₁-C₆-alkoxygroups; R⁹ and R¹⁰ are independently —OH, —C₁-C₆-alkoxy, halogen,heteroaryl, —NR^(d1)R^(d2) or —N(R¹²)(R¹³); R¹¹, R¹² and R¹³: areindependently a hydrogen atom, a C₁-C₆-alkyl, aryl, heteroaryl,cycloalkyl or heterocycloalkyl group, in which C₁-C₆-alkyl, aryl,heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of eachother, optionally substituted with one or more —(CH₂)_(o)R¹⁴ groups, orR¹² and R¹³, together with the N atom to which they are bound, form a5-, 6-, or 7-membered heterocyclic ring which optionally comprises oneor more additional heteroatoms, which optionally comprises one or more—C(═O)— or —S(═O)₂ groups, and which is optionally substituted with oneor more —(CH₂)_(o)R¹⁴ groups; R¹⁵ is, in each occurrence, independently,a halogen atom, a C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxyalkyl,cycloalkyl, heterocycloalkyl, —OR^(c), —NR^(d1)R^(d2), —CN, —NHS(═O)₂H,—NR^(a)S(═O)₂R^(b), —S(═O)₂R^(b) or —C(═O)R^(b) group; R¹⁵ is, in eachoccurrence, independently, a hydrogen atom or a C₁-C₆-alkyl group, inwhich at least one R¹⁵ groups is C₁-C₆-alkyl; n is, in each occurrence,independently, an integer of 0, 1, 2, 3, or 4; m is, in each occurrence,independently, an integer of 0, 1, or 2; and o is, in each occurrence,independently, an integer of 0, 1, or 2; R^(a) is, in each occurrence,independently, a hydrogen atom or a C₁-C₆-alkyl group; R^(b) is, in eachoccurrence, independently, an —OH, —OR^(C), —SR^(c), —NR^(d1)R^(d2), aC₁-C₆-alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, inwhich C₁-C₆-alkyl, heteroaryl, cycloalkyl and heterocycloalkyl are,independently of each other, optionally substituted one or more timeswith a halogen atom, an —OH, C1-C6-alkyl or C₁-C₆-alkoxy group; R^(c)is, in each occurrence, independently, a hydrogen atom, a —C(═O)R^(e),—S(═O)₂R^(e), C₁-C₆-alkyl, C₁-C₆-haloalkyl cycloalkyl, heterocycloalkyl,aryl, or heteroaryl group, in which C₁-C₆-alkyl, C₁-C₆-haloalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, are, independently ofeach other, optionally substituted one or more times with a halogenatom, an —OH, aryl, —OR^(f), —NR^(d1)R^(d2), or —OP(═O)(OR^(f))₂ group;R^(d1), R^(d2), R^(d1), R^(d2): are, in each occurrence, independentlyof each other, a hydrogen atom, a C₁-C₆-alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, —C(═O)R^(e), —S(═O)₂R^(e), or—C(═O)NR^(g1)R^(d2) group, in which C₁-C₆-alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl are, independently of each other,optionally substituted one or more times, the same way or differently,with a halogen atom, a C₁-C₆-alkyl, an —OH or aryl, —NR^(g1)R^(g2),—OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or —OP(═O)(OR^(f))₂ group; or R^(d1)and R^(d2), together with the nitrogen atom to which they are bound,form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl ring,which is optionally substituted one or more times, the same way ordifferently, with a halogen atom, a C₁-C₆-alkyl, —NR^(g1)R^(g2),—OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or —OP(═O)(OR^(f))₂ group; and thecarbon backbone of which is optionally interrupted one or more times, inthe same way or differently, with NH, NR^(d3), O, or S, and isoptionally interrupted one or more times, in the same way ordifferently, with a —C(═O)—, —S(═O)—, and/or —S(═O)₂-group, andoptionally contains one or more double bonds; R^(d3) is a hydrogen atom,a C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group,in which C₁-C₆-alkyl or cycloalkyl are, independently of each other,optionally substituted one or more times with a halogen atom, an —OH,C₁-C₆-alkyl, cycloalkyl, C₁-C₆-haloalkyl or C₁-C₆-alkoxy group; R^(e) isan —NR^(g1)R^(g2) ₅ C₁-C₆-alkyl, cycloalkyl, C₁-C₆-alkoxy, aryl orheteroaryl group; R^(f) is a hydrogen atom, a —C(═O)R^(e), C₁-C₆-alkyl,C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroarylgroup, in which C₁-C₆-alkyl, C₁-C₆-haloalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl are, independently of each other,optionally substituted one or more times with a halogen atom, an —OH,C₁-C₆-alkoxy, aryl, or —NR^(g1)R^(g2) group; R^(g1), R^(g2) are,independently of each other, a hydrogen atom, a C₁-C₆-alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl group; or R^(g1) and R^(g2)together with the nitrogen atom to which they are bound, form a 3-, 4-,5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl ring, which isoptionally substituted one or more times, in the same way ordifferently, with a halogen atom, an —OH, C₁-C₆-alkyl, C₁-C₆-alkoxygroup; and the carbon backbone of which is optionally interrupted one ormore times, in the same way or differently, with NH, NR^(a), O, S, andis optionally interrupted one or more times, in the same way ordifferently, with a —C(═O)—, —S(═O)—, and/or —S(═O)₂— group, andoptionally contains one or more double bonds; with the proviso that:X—R⁶ is not (O or NH)—(CH₂)_(r)—R^(r), where R^(r) is NR^(s1)R^(s2) inwhich r=1-4, and R^(s1), R^(s2)=independently hydrogen, C₁-C₈ alkyl, ortaken together with the nitrogen to which they are attached, form a 3-10member cyclic ring optionally containing one oxygen atom or one sulfuratom or one NH or N—C₁-C₈ alkyl group; or a tautomer, stereoisomer,physiologically acceptable salt, hydrate, solvate, metabolite, orprodrug thereof.
 2. The compound according to claim 1, wherein: R¹ andR² are the same or different and are independently a halogen atom, amethyl, or C₂-alkynyl group, in which at least one of R¹ and R² is ahalogen atom; R³ is, in each occurrence, a halogen atom; q is an integerof 1, 2, or 3; R⁴ is a hydrogen atom; R⁵ is a —C(═O)R⁷ or—C(═O)N(R⁷)(R⁸) group; X is —O—; R⁶ is —(CR¹⁵ ₂)_(n)—(CR¹⁵(OR¹¹))—(CR¹⁵₂)_(m)—R⁹, or —(CH₂)_(n)—Y; Y is: a) an aryl, heteroaryl, cycloalkyl orheterocycloalkyl group, said aryl, heteroaryl, cycloalkyl orheterocycloalkyl group being substituted with one or more —(CH₂)_(o)Y′groups, in each occurrence of said —(CH₂)_(o)Y′ group: o is an integerof 0; and Y′ is, independently: a C₁-C₆-alkyl, C₁-C₆-haloalkyl,C₁-C₆-alkoxyalkyl, cycloalkyl, or heterocycloalkyl group, or an —OR^(c′)group, in each occurrence of which, R^(c′) is, independently: a—C(═O)R^(e) group, in which R^(e) is defined infra, or an —S(═O)₂R^(e)group, in which R^(e) is defined infra, or a C₁-C₆-haloalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group, in whichC₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroarylgroup, are, independently of each other, optionally substituted one ormore times with:  a halogen atom, or  an —OH, or  an aryl group, or  an—OR^(f) group, in which R^(f) is as defined infra, or  an —NR^(d1)R^(d2)group, in which R^(d1) and R^(d2) are as defined infra, or  a—OP(═O)(OR^(f))₂ group, in which R^(f) is as defined infra; or an—NR^(d1)R^(d2) group, as defined infra, with the provisos that: when oneof R^(d1) and R^(d2) is H, then the other of R^(d1) and R^(d2) isneither H nor C₁-C₆-alkyl, and R^(d1) and R^(d2) cannot simultaneouslybe C₁-C₆-alkyl; or an —NR^(a)S(═O)₂R^(b) group, as defined infra, withthe proviso that:  when R_(a) is H, then R_(b) is not C₁-C₆-alkyl; or an—S(═O)₂R^(b) group, in which R^(b) is as defined infra, with theprovisos that when R^(b) is —NR^(d1)R^(d2):  R^(d1) and R^(d2) are notboth H,  when R^(d1) is H, then R^(d2) is not C₁-C₆-alkyl,  R^(d1) andR^(d2) are not both C₁-C₆-alkyl, or a —C(═O)R^(b) group, in which R^(b)is as defined infra; or b) an aryl, heteroaryl, cycloalkyl orheterocycloalkyl group, said aryl, heteroaryl, cycloalkyl orheterocycloalkyl group being substituted with one or more —(CH₂)_(o)R¹⁴groups, in each occurrence of said —(CH₂)_(o)R¹⁴ group: o is an integerof 1 or 2; and R¹⁴ is as defined infra; or c) a C₂-C₁₀-alkenyl orC₅-C₁₀-cycloalkenyl group, said C₂-C₁₀-alkenyl or C₅-C₁₀-cycloalkenylgroup being optionally substituted with one or more —(CH₂)_(o)R¹⁴groups, in which o and R¹⁴ are as defined infra; R⁷ and R⁸ areindependently a hydrogen atom, a —N(R¹²)(R¹³), —OH, —C₁-C₆-alkoxy,—C₁-C₆-alkyl, —CF₃, —O—(CH₂)_(n)—(CH(OR¹¹))—(CH₂)_(m)—R⁹,—O—(CH₂)_(n)-cycloalkyl, aryl, heteroaryl, cycloalkyl orheterocycloalkyl group, in which aryl, heteroaryl, cycloalkyl, orheterocycloalkyl are, independently of each other, optionallysubstituted with one or more halogen atoms, C₁-C₆-alkyl or C₁-C₆-alkoxygroups; R⁹ and R¹⁰ are independently —OH, —C₁-C₆-alkoxy, halogen,heteroaryl, —NR^(d1)R^(d2) or —N(R¹²)(R¹³); R¹¹, R¹² and R¹³: areindependently a hydrogen atom, a C₁-C₆-alkyl, aryl, heteroaryl,cycloalkyl or heterocycloalkyl group, in which C₁-C₆-alkyl, aryl,heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of eachother, optionally substituted with one or more —(CH₂)_(o)R¹⁴ groups, orR¹² and R¹³, together with the N atom to which they are bound, form a5-, 6-, or 7-membered heterocyclic ring which optionally comprises oneor more additional heteroatoms, which optionally comprises one or more—C(═O)— or —S(═O)₂ groups, and which is optionally substituted with oneor more —(CH₂)_(o)R¹⁴ groups; R¹⁴ is, in each occurrence, independently,a halogen atom, a C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxyalkyl,cycloalkyl, heterocycloalkyl, —OR^(c), —NR^(d1)R^(d2), —CN, —NHS(═O)₂H,—NR^(a)S(═O)₂R^(b), —S(═O)₂R^(b) or —C(═O)R^(b) group; R¹⁵ is, in eachoccurrence, independently, a hydrogen atom or a C₁-C₆-alkyl group, inwhich at least one R¹⁵ groups is C₁-C₆-alkyl; n is, in each occurrence,independently, an integer of 0, 1, 2, 3, or 4; m is, in each occurrence,independently, an integer of 0, 1, or 2; and o is, in each occurrence,independently, an integer of 0, 1, or 2; R^(a) is, in each occurrence,independently, a hydrogen atom or a C₁-C₆-alkyl group; R^(b) is, in eachoccurrence, independently, an —OH, —OR^(C), —SR^(c), —NR^(d1)R^(d2), aC₁-C₆-alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, inwhich C₁-C₆-alkyl, heteroaryl, cycloalkyl and heterocycloalkyl are,independently of each other, optionally substituted one or more timeswith a halogen atom, an —OH, C1-C6-alkyl or C₁-C₆-alkoxy group; R^(c)is, in each occurrence, independently, a hydrogen atom, a —C(═O)R^(e),—S(═O)₂R^(e), C₁-C₆-alkyl, C₁-C₆-haloalkyl cycloalkyl, heterocycloalkyl,aryl, or heteroaryl group, in which C₁-C₆-alkyl, C₁-C₆-haloalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, are, independently ofeach other, optionally substituted one or more times with a halogenatom, an —OH, aryl, —OR^(f), —NR^(d1)R^(d2), or —OP(═O)(OR^(f))₂ group;R^(d1), R^(d2), R^(d1), R^(d2): are, in each occurrence, independentlyof each other, a hydrogen atom, a C₁-C₆-alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, —C(═O)R^(e), —S(═O)₂R^(e), or—C(═O)NR^(g1)R^(g2) group, in which C₁-C₆-alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl are, independently of each other,optionally substituted one or more times, the same way or differently,with a halogen atom, a C₁-C₆-alkyl, an —OH or aryl, —NR^(g1)R^(g2),—OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or —OP(═O)(OR^(f))₂ group; or R^(d1)and R^(d2), together with the nitrogen atom to which they are bound,form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl ring,which is optionally substituted one or more times, the same way ordifferently, with a halogen atom, a C₁-C₆-alkyl, —NR^(g1)R^(g2),—OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or —OP(═O)(OR^(f))₂ group; and thecarbon backbone of which is optionally interrupted one or more times, inthe same way or differently, with NH, NR^(d3), O, or S, and isoptionally interrupted one or more times, in the same way ordifferently, with a —C(═O)—, —S(═O)—, and/or —S(═O)₂-group, andoptionally contains one or more double bonds; R^(d3) is a hydrogen atom,a C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group,in which C₁-C₆-alkyl or cycloalkyl are, independently of each other,optionally substituted one or more times with a halogen atom, an —OH,C₁-C₆-alkyl, cycloalkyl, C₁-C₆-haloalkyl or C₁-C₆-alkoxy group; R^(e) isan —NR^(g1)R^(g2), C₁-C₆-alkyl, cycloalkyl, C₁-C₆-alkoxy, aryl orheteroaryl group; R^(f) is a hydrogen atom, a —C(═O)R^(e), C₁-C₆-alkyl,C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroarylgroup, in which C₁-C₆-alkyl, C₁-C₆-haloalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl are, independently of each other,optionally substituted one or more times with a halogen atom, an —OH,C₁-C₆-alkoxy, aryl, or —NR^(g1)R^(g2) group; R^(g1), R^(g2) are,independently of each other, a hydrogen atom, a C₁-C₆-alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl group; or R^(g1) and R^(g2)together with the nitrogen atom to which they are bound, form a 3-, 4-,5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl ring, which isoptionally substituted one or more times, in the same way ordifferently, with a halogen atom, an —OH, C₁-C₆-alkyl, C₁-C₆-alkoxygroup; and the carbon backbone of which is optionally interrupted one ormore times, in the same way or differently, with NH, NR^(a), O, S, andis optionally interrupted one or more times, in the same way ordifferently, with a —C(═O)—, —S(═O)—, and/or —S(═O)₂— group, andoptionally contains one or more double bonds; with the proviso that:X—R⁶ is not (O or NH)—(CH₂)_(r)—R^(r), where R^(r) is NR^(s1)R^(s2) inwhich r=1-4, and R^(s1), R^(s2)=independently hydrogen, C₁-C₈ alkyl, ortaken together with the nitrogen to which they are attached, form a 3-10member cyclic ring optionally containing one oxygen atom or one sulfuratom or one NH or N—C₁-C₈ alkyl group; or a tautomer, stereoisomer,physiologically acceptable salt, hydrate, solvate, metabolite, orprodrug thereof.
 3. The compound according to claim 1, wherein: R¹ andR² are the same or different and are independently a halogen atom, amethyl, or C₂-alkynyl group, in which at least one of R¹ and R² is ahalogen atom; R³ is, in each occurrence, a halogen atom; q is an integerof 1, 2, or 3; R⁴ is a hydrogen atom; R⁵ is a —C(═O)NH₂ group; X is —O—;R⁶ is —(CH₂)_(n)—Y; Y is an aryl or heteroaryl group, said aryl orheteroaryl group being substituted with a —(CH₂)_(o)Y′ group, in eachoccurrence of said —(CH₂)_(o)Y′ group: o is an integer of 0; and Y′ is,independently: an —NR^(d1)R^(d2) group, as defined infra, with theprovisos that: when one of R^(d1) and R^(d2) is H, then the other ofR^(d1) and R^(d2) is neither H nor C₁-C₆-alkyl, and R^(d1) and R^(d2)cannot simultaneously be C₁-C₆-alkyl; or an —NR^(a)S(═O)₂R^(b) group, asdefined infra, with the proviso that: when R_(a) is H, then R_(b) is notC₁-C₆-alkyl; R⁷ and R⁸ are independently a hydrogen atom, a—N(R¹²)(R¹³), —OH, —C₁-C₆-alkoxy, —C₁-C₆-alkyl, —CF₃,—O—(CH₂)_(n)—(CH(OR¹¹))—(CH₂)_(m)—R⁹, —O—(CH₂)_(n)-cycloalkyl, aryl,heteroaryl, cycloalkyl or heterocycloalkyl group, in which aryl,heteroaryl, cycloalkyl, or heterocycloalkyl are, independently of eachother, optionally substituted with one or more halogen atoms,C₁-C₆-alkyl or C₁-C₆-alkoxy groups; R⁹ and R¹⁰ are independently —OH,—C₁-C₆-alkoxy, halogen, heteroaryl, —NR^(d1)R^(d2) or —N(R¹²)(R¹³); R¹¹,R¹² and R¹³: are independently a hydrogen atom, a C₁-C₆-alkyl, aryl,heteroaryl, cycloalkyl or heterocycloalkyl group, in which C₁-C₆-alkyl,aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are, independently ofeach other, optionally substituted with one or more —(CH₂)_(o)R¹⁴groups, or R¹² and R¹³, together with the N atom to which they arebound, form a 5-, 6-, or 7-membered heterocyclic ring which optionallycomprises one or more additional heteroatoms, which optionally comprisesone or more —C(═O)— or —S(═O)₂ groups, and which is optionallysubstituted with one or more —(CH₂)_(o)R¹⁴ groups; R¹⁴ is, in eachoccurrence, independently, a halogen atom, a C₁-C₆-alkyl,C₁-C₆-haloalkyl, C₁-C₆-alkoxyalkyl, cycloalkyl, heterocycloalkyl,—OR^(c), —NR^(d1)R^(d2), —CN, —NHS(═O)₂H, —NR^(a)S(═O)₂R^(b),—S(═O)₂R^(b) or —C(═O)R^(b) group; R¹⁵ is, in each occurrence,independently, a hydrogen atom or a C₁-C₆-alkyl group, in which at leastone R¹⁵ groups is C₁-C₆-alkyl; n is, in each occurrence, independently,an integer of 0, 1, 2, 3, or 4; m is, in each occurrence, independently,an integer of 0, 1, or 2; and o is, in each occurrence, independently,an integer of 0, 1, or 2; R^(a) is, in each occurrence, independently, ahydrogen atom or a C₁-C₆-alkyl group; R^(b) is, in each occurrence,independently, an —OH, —OR^(c), —SR^(c), —NR^(d1)R^(d2), a C₁-C₆-alkyl,aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, in whichC₁-C₆-alkyl, heteroaryl, cycloalkyl and heterocycloalkyl are,independently of each other, optionally substituted one or more timeswith a halogen atom, an —OH, C1-C6-alkyl or C₁-C₆-alkoxy group; R^(c)is, in each occurrence, independently, a hydrogen atom, a —C(═O)R^(e),—S(═O)₂R^(e), C₁-C₆-alkyl, C₁-C₆-haloalkyl cycloalkyl, heterocycloalkyl,aryl, or heteroaryl group, in which C₁-C₆-alkyl, C₁-C₆-haloalkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, are, independently ofeach other, optionally substituted one or more times with a halogenatom, an —OH, aryl, —OR^(f), —NR^(d1)R^(d2), or —OP(═O)(OR^(f))₂ group;R^(d1), R^(d2), R^(d1), R^(d2): are, in each occurrence, independentlyof each other, a hydrogen atom, a C₁-C₆-alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, —C(═O)R^(e), —S(═O)₂R^(e), or—C(═O)NR^(g1)R^(g2) group, in which C₁-C₆-alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl are, independently of each other,optionally substituted one or more times, the same way or differently,with a halogen atom, a C₁-C₆-alkyl, an —OH or aryl, —NR^(g1)R^(g2),—OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or —OP(═O)(OR^(f))₂ group; or R^(d1)and R^(d2), together with the nitrogen atom to which they are bound,form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl ring,which is optionally substituted one or more times, the same way ordifferently, with a halogen atom, a C₁-C₆-alkyl, —NR^(g1)R^(g2),—OR^(f), —C(═O)R^(e), —S(═O)₂R^(e), or —OP(═O)(OR^(f))₂ group; and thecarbon backbone of which is optionally interrupted one or more times, inthe same way or differently, with NH, NR^(d3), O, or S, and isoptionally interrupted one or more times, in the same way ordifferently, with a —C(═O)—, —S(═O)—, and/or —S(═O)₂-group, andoptionally contains one or more double bonds; R^(d3) is a hydrogen atom,a C₁-C₆-alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group,in which C₁-C₆-alkyl or cycloalkyl are, independently of each other,optionally substituted one or more times with a halogen atom, an —OH,C₁-C₆-alkyl, cycloalkyl, C₁-C₆-haloalkyl or C₁-C₆-alkoxy group; R^(e) isan —NR^(g1)R^(g2), C₁-C₆-alkyl, cycloalkyl, C₁-C₆-alkoxy, aryl orheteroaryl group; R^(f) is a hydrogen atom, a —C(═O)R^(e), C₁-C₆-alkyl,C₁-C₆-haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroarylgroup, in which C₁-C₆-alkyl, C₁-C₆-haloalkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl are, independently of each other,optionally substituted one or more times with a halogen atom, an —OH,C₁-C₆-alkoxy, aryl, or —NR^(g1)R^(g2) group; R^(g1), R^(g2) are,independently of each other, a hydrogen atom, a C₁-C₆-alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl group; or R^(g1) and R^(g2)together with the nitrogen atom to which they are bound, form a 3-, 4-,5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl ring, which isoptionally substituted one or more times, in the same way ordifferently, with a halogen atom, an —OH, C₁-C₆-alkyl, C₁-C₆-alkoxygroup; and the carbon backbone of which is optionally interrupted one ormore times, in the same way or differently, with NH, NR^(a), O, S, andis optionally interrupted one or more times, in the same way ordifferently, with a —C(═O)—, —S(═O)—, and/or —S(═O)₂— group, andoptionally contains one or more double bonds; with the proviso that:X—R⁶ is not (O or NH)—(CH₂)_(r)—R^(r), where R^(r) is NR^(s1)R^(s2) inwhich r=1-4, and R^(s2), R^(s2)=independently hydrogen, C₁-C₈ alkyl, ortaken together with the nitrogen to which they are attached, form a 3-10member cyclic ring optionally containing one oxygen atom or one sulfuratom or one NH or N—C₁-C₈ alkyl group; or a tautomer, stereoisomer,physiologically acceptable salt, hydrate, solvate, metabolite, orprodrug thereof.
 4. The compound according to claim 1, which is selectedfrom the group consisting of:{3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamicacid tert-butyl ester;{3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamicacid tert-butyl ester;2-[3-[[(Dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;4-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phthalicacid;4-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phthalicacid 2-methyl ester;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(6-trifluoromethyl-pyridin-2-yloxy)-benzamide;2-{3-[(Dimethylsulfamoyl)amino]phenoxy}-4-fluoro-6-[(4-iodophenyl)amino]benzamide;2-{3-[(Dimethylsulfamoyl)amino]phenoxy}-4-fluoro-6-[(4-iodo-2-methylphenyl)amino]benzamide;6-{3-[(Dimethylsulfamoyl)amino]phenoxy}-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide;{3-[2-Carbamoyl-4,5,6-trifluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-carbamicacid tert-butyl ester;2-{3-[(dimethylsulfamoyl)amino]phenoxy}-3,4,5-trifluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;2-[3-(3,3-Dimethyl-ureido)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;3-{3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-1,1-dimethyl-urea;2-(3-Aminomethyl-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;compound with formic acid; Dimethyl-carbamic acid3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenylester;2-(4-Acetylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-N-ethyl-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-N-methyl-benzamide;2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxy-ethyl)-benzamide;2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxy-propyl)-benzamide;2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-N-((R)-2-hydroxy-1-methyl-ethyl)-benzamide;2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-N-((S)-2-hydroxy-1-methyl-ethyl)-benzamide;2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-N-((R)-2-hydroxy-propyl)-benzamide;2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-N-((S)-2-hydroxy-propyl)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-pentafluoroethyl-phenoxy)-benzamide;2-(3-Cyclohexylsulfamoyl-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;{3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-benzyl}-carbamicacid tert-butyl ester;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-sulfamoylmethyl-phenoxy)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-methanesulfonylmethyl-phenoxy)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(6-trifluoromethyl-pyridin-2-yloxy)-benzonitrile;5-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-nicotinicacid methyl ester;2-(3-Carbamoyl-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;{3-[3-(4-Bromo-2-fluoro-phenylamino)-2-carbamoyl-5-fluoro-phenoxy]-phenyl}-carbamicacid tert-butyl ester;2-[3-[[(propylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;2-(3-Acetylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenyl-amino)-benzamide;2-[3-(3-Chloro-propane-1-sulfonylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-bis-methanesulfonyl-amino-phenoxy)-benzamide;2-[3-(1,1-Dioxo-1λ6-isothiazolidin-2-yl)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-[3-[[(amino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(morpholine-4-sulfonylamino)-phenoxy]-benzamide;2-(3-Cyclopropanesulfonylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-(3-Cyclopentanesulfonylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-(3-diethylsulfamoyl-amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(pyrrolidine-1-sulfonylamino)-phenoxy]-benzamide;2-[3-[[(methylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(4H-[1,2,4]triazole-3-sulfonylamino)-phenoxy]-benzamide;2-(3-Cyclobutanesulfonylamino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(1H-imidazole-4-sulfonylamino)-phenoxy]-benzamide;2-[3-[[(di-2-methoxyethylylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(1-methyl-1H-pyrazole-4-sulfonylamino)-phenoxy]-benzamide;2-[3-(1,1-Dioxo-tetrahydro-1λ6-thiophene-3-sulfonylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;6-[3-(aminosulfonylamino-methyl)-phenoxy]-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-benzamide;6-[3-(dimethylaminosulfonylamino-methyl)-phenoxy]-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[3-(methanesulfonylamino-methyl)-phenoxy]-benzamide;2-[3-(Acetylamino-methyl)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-[3-(2,2-Dimethyl-propionylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-[3-(Cyclopropanecarbonyl-amino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-[3-(Cyclopentanecarbonyl-amino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;Thiophene-3-carboxylic acid{3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-amide;[1,2,3]Thiadiazole-4-carboxylic acid{3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-amide;Furan-3-carboxylic acid{3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-amide;Isoxazole-5-carboxylic acid{3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-amide;1H-Pyrazole-4-carboxylic acid{3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-amide;2-[3-(Cyclobutanecarbonyl-amino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;1H-Pyrazole-3-carboxylic acid{3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-amide;3-Methyl-3H-imidazole-4-carboxylic acid{3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-amide;3-Methyl-isoxazole-4-carboxylic acid{3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-amide;Isoxazole-3-carboxylic acid{3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-amide;N-{3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-isonicotinamide;2-[3-(2-Chloro-propane-2-sulfonylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;1-Methyl-1H-pyrrole-2-carboxylic acid{3-[2-carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-phenyl}-amide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-isobutyrylamino-phenoxy)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-{3-[(1-hydroxy-cyclopropanecarbonyl)-amino]-phenoxy}-benzamide;2-[5-(1,1-Dioxo-tetrahydro-1λ6-thiophene-3-sulfonylamino)-pyridin-3-yloxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[5-(1H-imidazole-4-sulfonylamino)-pyridin-3-yloxy]-benzamide;4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-(3-{[(2,2,2-trifluoroethyl)sulfamoyl]amino}phenoxy)benzamide;4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-(3-{[(2-methoxyethyl)sulfonyl]amino}phenoxy)benzamide;2-[3-(2,3-Dihydroxy-propane-1-sulfonylamino)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-[3-[[(dimethylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(4-ethynyl-2-fluorophenyl)amino]-benzamide;2-[3-[[(propylamino)sulfonyl]amino]phenoxy]-4-fluoro-6-[(4-ethynyl-2-fluorophenyl)amino]-benzamide;2-{3-[(dimethylsulfamoyl)amino]phenoxy}-6-[(4-ethynyl-2-fluorophenyl)amino]-3,4,5-trifluorobenzamide;6-[3-[[(dimethylamino)sulfonyl](methyl)-amino]phenoxy]-4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide;3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-benzoicacid;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-methanesulfonyl-phenoxy)-benzamide;and2-[3-(3,3-Dimethyl-ureido)-phenoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide.5. The compound according to claim 1, which is selected from the groupconsisting of:2-(Cyclopent-3-enyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrile;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(4-methyl-pent-3-enyloxy)-benzonitrile;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-methyl-but-3-enyloxy)-benzonitrile;3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester;2-{2-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester;3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-piperidine-1-carboxylicacid tert-butyl ester;2-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-morpholine-4-carboxylicacid tert-butyl ester;3-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-azetidine-1-carboxylicacid tert-butyl ester;4-[2-Cyano-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(4-methyl-pent-3-enyloxy)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(3-methyl-but-3-enyloxy)-benzamide;2-(Cyclopent-3-enyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester;2-{2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester;3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-piperidine-1-carboxylicacid tert-butyl ester;2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-morpholine-4-carboxylicacid tert-butyl ester;3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-azetidine-1-carboxylicacid tert-butyl ester;4-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-piperidine-1-carboxylicacid tert-butyl ester;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methyl-piperidin-4-yloxy)-benzamide;4-{2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-ethyl}-piperazine-1-carboxylicacid tert-butyl ester;6-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-indole-1-carboxylicacid tert-butyl ester;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[4-(methanesulfonyl-methyl-amino)-phenoxy]-benzamide;2-[2-((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;(R)-2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester;(S)-2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester;{4-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-cyclohexyl}-carbamicacid tert-butyl ester;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-((S)-1-methyl-pyrrolidin-2-ylmethoxy)-benzamide;2-((RS)-1-Ethyl-pyrrolidin-2-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methyl-1H-pyrazol-4-yloxy)-benzamide;3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-piperazine-1-carboxylicacid tert-butyl ester;2-(1,4-Dimethyl-piperazin-2-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-{2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-ethyl}-piperidine-1-carboxylicacid dimethylamide;2-[2-(1-Ethanesulfonyl-piperidin-2-yl)-ethoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-(1-Benzenesulfonyl-piperidin-3-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methanesulfonyl-piperidin-3-ylmethoxy)-benzamide;2-(1-Ethanesulfonyl-piperidin-3-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[2-(1-methanesulfonyl-piperidin-2-yl)-ethoxy]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methanesulfonyl-pyrrolidin-3-ylmethoxy)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methanesulfonyl-piperidin-4-yloxy)-benzamide;4-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-piperidine-1-carboxylicacid dimethylamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[1-(1H-imidazole-4-sulfonyl)-azetidin-3-ylmethoxy]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methanesulfonyl-azetidin-3-ylmethoxy)-benzamide;2-[2-(1-Cyclopropanesulfonyl-piperidin-2-yl)-ethoxy]-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-(1-Acetyl-piperidin-4-yloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-piperidine-1-carboxylicacid ethyl ester;4-{2-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxy]-ethyl}-piperazine-1-carboxylicacid dimethylamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[2-(4-methanesulfonyl-piperazin-1-yl)-ethoxy]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(R)-1-methanesulfonyl-pyrrolidin-2-ylmethoxy)-benzamide;2-((R)-1-Ethanesulfonyl-pyrrolidin-2-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-((S)-1-Ethanesulfonyl-pyrrolidin-2-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-(4-dimethylsulfamoylamino-cyclohexyloxy)-4-Fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-((R)-1-Acetyl-pyrrolidin-2-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[(R)-1-(imidazole-1-carbonyl)-pyrrolidin-2-ylmethoxy]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[(S)-1-(imidazole-1-carbonyl)-pyrrolidin-2-ylmethoxy]-benzamide;2-(1-Acetyl-azetidin-3-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(4-methanesulfonyl-morpholin-2-ylmethoxy)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methanesulfonyl-pyrrolidin-3-ylmethoxy)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[1-(morpholine-4-sulfonyl)-pyrrolidin-3-ylmethoxy]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[1-(1H-imidazole-4-sulfonyl)-piperidin-3-ylmethoxy]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[1-(4H-[1,2,4]triazole-3-sulfonyl)-piperidin-3-ylmethoxy]-benzAmide;2-(1-Acetyl-piperidin-3-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[1-(1-methyl-1H-pyrazole-4-sulfonyl)-azetidin-3-ylmethoxy]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[1-(1-methyl-1H-imidazole-4-sulfonyl)-azetidin-3-ylmethoxy]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-3-ylmethoxy]-benzamide;3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-4-methanesulfonyl-piperazine-1-carboxylicacid tert-butyl ester;3-[2-Carbamoyl-5-fluoro-3-(2-fluoro-4-iodo-phenylamino)-phenoxymethyl]-pyrrolidine-1-sulfonicacid;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[4-(1-methyl-1H-imidazole-4-sulfonyl)-morpholin-2-ylmethoxy]-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[4-(1-methyl-1H-pyrazole-4-sulfonyl)-morpholin-2-ylmethoxy]-benzamide;4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-{1-(methylsulfonyl)piperazin-2-yl]methoxy}-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-[4-(1H-imidazole-4-sulfonyl)-morpholin-2-ylmethoxy]-benzamide;2-({4-[bis(2-methoxyethyl)sulfamoyl]morpholin-2-yl}methoxy)-4-fluoro-6-[(2-fluoro-4-iodophenyl)amino]-benzamide;4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-{[4-(morpholin-4-ylsulfonyl)morpholin-2-yl]methoxy}-benzamide;2-(1-Acetyl-piperazin-2-ylmethoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-6-(1-methyl-piperazin-2-ylmethoxy)-benzamide;2-(3,4-Dihydroxy-4-methyl-pentyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-(3,4-Dihydroxy-3-methyl-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-(3,4-Dihydroxy-4-methyl-pentyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-(3,4-Dihydroxy-3-methyl-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;2-(3,4-Dihydroxy-4-methyl-pentyloxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrile;2-(3,4-Dihydroxy-3-methyl-butoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzonitrile;6-(3,4-Dihydroxy-4-methyl-pentyloxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide;2-(3,4-Dihydroxy-4-methyl-pentyloxy)-3,4,5-trifluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide;and2-((R)-3,4-Dihydroxy-4-methyl-pentyloxy)-6-(4-ethynyl-2-fluoro-phenylamino)-4-fluoro-benzamide.6. A method of preparing a compound of general formula (I) according toclaim 1, said method comprising the step of allowing an intermediatecompound of general formula Ia:

in which R¹, R², R³, R⁵, R^(6a), X and q are as defined in claim 1, toreact with an acid, for example hydrochloric acid or TFA thereby givinga compound of formula I:

in which R¹, R², R³, R⁵, R⁶, X and q are as defined in claim
 1. 7. Amethod of preparing a compound of general formula (Ic) according toclaim 1, said method comprising the step of allowing an intermediatecompound of general formula Ib:

in which R¹, R², R³, R^(6a), X and q are as defined in claim 1, to reactwith an acid, for example hydrochloric acid or TFA thereby giving acompound of formula Ic:

in which R¹, R², R³, R^(6a), X and q are as defined in claim
 1. 8. Amethod of preparing a compound of general formula (Ig) according toclaim 1, said method comprising the step of allowing an intermediatecompound of general formula If:

in which R¹, R³, R⁵, R^(6a), X and q are as defined in claim 1, to reactwith a deprotecting agent thereby giving a compound of formula Ig:

in which R¹, R³, R⁵, R⁶, X and q are as defined in claim
 1. 9. A methodof preparing a compound of general formula (Iv) according to claim 1,said method comprising the step of allowing an intermediate compound ofgeneral formula Iu:

in which R¹, R³, R⁵, X and q are as defined in claim 1, to react with asulfonyl chloride of formula bb

in which R^(b) is as defined in claim 1; thereby giving a compound offormula Iv:

in which R¹, R³, R⁵, X, R^(n) and q are as defined in claim
 1. 10. Apharmaceutical composition comprising a compound according to claim 1,or a tautomer, stereoisomer, physiologically acceptable salt, hydrate,solvate, metabolite, or prodrug thereof, and a pharmaceuticallyacceptable diluent or carrier.
 11. The pharmaceutical compositionaccording to claim 10 wherein said compound is present in atherapeutically effective amount.
 12. The pharmaceutical compositionaccording to claim 11 which further comprises at least one furtheractive compound.
 13. The pharmaceutical composition according to claim12, in which said further active compound is an anti-hyperproliferativeagent, an anti-angiogenic agent, a mitotic inhibitor, an alkylatingagent, an anti-metabolite, a DNA-intercalating antibiotic, a growthfactor inhibitor, a cell cycle inhibitor, an enzyme inhibitor, atoposisomerase inhibitor, a biological response modifier, or ananti-hormone.
 14. (canceled)
 15. A method of inhibiting mitogenextracellular kinase enzymes in a cell comprising contacting a cell withone or more compounds according to claim
 1. 16. The method according toclaim 15, wherein said cell is a mammalian cell. 17-24. (canceled)
 25. Amethod of treating a hyperproliferative disorder, an angiogenesisdisorder, or abnormal cell growth comprising administering to a mammalin need thereof a therapeutically effective amount of a compoundaccording to claim
 1. 26. The method according to claim 25, wherein saidhyperproliferative disorder is cancer, psoriasis, restenosis, autoimmunedisease, atherosclerosis, rheumatoid arthritis, chronic pain,neuropathic pain, osteoarthritis, benign prostate hyperplasia, orhyperproliferative disease of the eye.
 27. The method according to claim26, wherein said cancer is a cancer of the breast, respiratory tract,brain, reproductive organs, digestive tract, urinary tract, eye, liver,skin, head and neck, endocrine system or a distant metastasis of a solidtumor.
 28. The method according to claim 27, wherein said cancer is asarcoma, a melanoma, a hematological malignancy, lymphoma, leukaemia ormultiple myeloma.
 29. The method according to claim 26, wherein saidhyperproliferative disease of the eye is cataract, conjunctivalepithelial cell hypermitosis or goblet cell hyperplasia.